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Tauch S, Hey J, Kast B, Gengenbacher N, Weiß L, Sator‐Schmitt M, Lohr S, Brobeil A, Schirmacher P, Utikal J, Augustin HG, Plass C, Angel P. A Unique Signature for Cancer-Associated Fibroblasts in Melanoma Metastases. Pigment Cell Melanoma Res 2025; 38:e70002. [PMID: 39924882 PMCID: PMC11808227 DOI: 10.1111/pcmr.70002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 11/27/2024] [Accepted: 01/16/2025] [Indexed: 02/11/2025]
Abstract
Cancer-associated fibroblasts (CAFs) represent a central cell population of the tumor microenvironment (TME). Recently, single-cell RNA-sequencing (scRNA-seq) analyses of primary tumors of different cancer entities yielded different classifications of CAF subsets underscoring the heterogeneity of CAFs within the TME. Here, we analyzed the transcriptional signatures of approximately 8400 CAFs and normal fibroblasts by scRNA-seq and compared genetic profiles of CAFs from murine melanoma primary tumors to CAFs from corresponding melanoma lung metastases. This revealed distinct subsets for primary tumor and metastasis-specific CAF populations, respectively. Combined with the spatial characterization of metastasis CAFs at the RNA and protein level, scRNA analyses indicate tumor-dependent crosstalk between neutrophils and CAFs, mediated via SAA3 and IL1b-related signaling pathways, which can be recapitulated in vitro. Analyzing tissue sections of human patient samples, this interaction was found to be present in human melanoma metastasis. Taken together, our data highlight unique characteristics of metastasis CAFs with potential therapeutic impact for melanoma metastasis.
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Affiliation(s)
- Saskia Tauch
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
- Faculty of BiosciencesHeidelberg UniversityHeidelbergGermany
| | - Joschka Hey
- Division of Cancer EpigenomicsGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Bettina Kast
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Nicolas Gengenbacher
- Division of Vascular Oncology and MetastasisGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
- European Center for Angioscience (ECAS), Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- DKFZ‐Hector Cancer Institute, University Medical Centre MannheimMannheimGermany
| | - Lena Weiß
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Melanie Sator‐Schmitt
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Sabrina Lohr
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
| | - Alexander Brobeil
- Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Peter Schirmacher
- Institute of PathologyUniversity Hospital HeidelbergHeidelbergGermany
| | - Jochen Utikal
- DKFZ‐Hector Cancer Institute, University Medical Centre MannheimMannheimGermany
- Skin Cancer UnitGerman Cancer Research Center (DKFZ)HeidelbergGermany
- Department of Dermatology, Venereology and AllergologyUniversity Medical Center Mannheim, Ruprecht‐Karl University of HeidelbergMannheimGermany
| | - Hellmut G. Augustin
- Division of Vascular Oncology and MetastasisGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
- European Center for Angioscience (ECAS), Medical Faculty MannheimHeidelberg UniversityMannheimGermany
- DKFZ‐Hector Cancer Institute, University Medical Centre MannheimMannheimGermany
| | - Christoph Plass
- Division of Cancer EpigenomicsGerman Cancer Research Center (DKFZ)HeidelbergGermany
| | - Peter Angel
- Division Signal Transduction and Growth ControlGerman Cancer Research Center (DKFZ‐ZMBH Alliance)HeidelbergGermany
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Gu Y, Zhou Z, Zhao X, Ye X, Qin K, Liu J, Zhang X, Ji Y. Inflammatory burden index (IBI) and body roundness index (BRI) in gallstone risk prediction: insights from NHANES 2017-2020. Lipids Health Dis 2025; 24:63. [PMID: 39985035 PMCID: PMC11844043 DOI: 10.1186/s12944-025-02472-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2025] [Accepted: 02/07/2025] [Indexed: 02/23/2025] Open
Abstract
BACKGROUND The Inflammatory Load Index (IBI) and Body Roundness Index (BRI) were employed to evaluate the systemic inflammatory status and body fat. This study aims to elucidate the association between IBI and the prevalence of gallstones, as well as to analyze the mediating role of BRI in this association. METHODS Data from the National Health and Nutrition Examination Survey (NHANES) (2017-2020) were utilized in our cross-sectional study. A total of 2598 participants aged ≥ 20 years were enrolled. The Boruta algorithm, a supervised classification feature selection method, is leveraged to identify the confounding variables most strongly associated with the prevalence of gallstones. Weighted multivariate logistic regression, restricted cubic splines (RCS), and subgroup analyses were employed to investigate the association between IBI and gallstones, assess the presence of a linear association, and evaluate the effect of IBI on gallstone risk across different populations. Finally, the mediating effect of BRI was examined. RESULTS In the fully adjusted model, when IBI was in the highest tertile, each unit increase in IBI (corresponding to an increase of 1 in the natural logarithm of IBI) was linked to a 110.8% higher prevalence of gallstones (OR = 2.108, 95% CI: 1.109-4.005; P = 0.028). The odds ratio for gallstones increased with higher IBI levels across unadjusted, partially adjusted, and fully adjusted models (P for trend < 0.05). This positive association was confirmed to be linear by the RCS curve (P for nonlinear = 0.887). Subgroup analysis indicated that the risk of gallstones was significantly elevated in individuals aged ≥ 60, females, and those with a Poverty-to-Income Ratio (PIR) ≥ 2 (P < 0.05). Mediation analysis revealed that IBI had a significant indirect effect on gallstone prevalence through BRI, with an effect size of 0.0129 (95% CI: 0.0121-0.0136; P < 0.001), and the mediation contributed to 33.24% of the total effect. CONCLUSIONS This study demonstrates a significant linear positive relation of IBI to gallstone prevalence. Furthermore, BRI mediates the effect of IBI on gallstone risk. These findings provide a more precise inflammatory marker for gallstone prevention and treatment. TRIAL REGISTRATION Not applicable.
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Affiliation(s)
- Yuting Gu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Zhanyi Zhou
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xuan Zhao
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiaolu Ye
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Keyi Qin
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Jiahui Liu
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Xiao Zhang
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China
| | - Yunxi Ji
- The First School of Clinical Medicine, Zhejiang Chinese Medical University, Hangzhou, 310053, China.
- Department of General Practice, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, 310053, China.
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Kim CH. Functional regulation of cytotoxic T cells by gut microbial metabolites. GUT MICROBES REPORTS 2025; 2:1-16. [PMID: 40115123 PMCID: PMC11922538 DOI: 10.1080/29933935.2025.2454002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Revised: 12/21/2024] [Accepted: 01/09/2025] [Indexed: 03/23/2025]
Abstract
Metabolites from gut microbes have a wide range of functions within the host body. One important function of these metabolites is to either positively or negatively control CD8+ cytotoxic T lymphocytes (CTLs), which can kill cancer and virus-infected cells. In healthy conditions, gut microbes produce a mixture of metabolites that promote CTL activity but also suppress excessive inflammatory responses. However, gut microbial dysbiosis occurs in patients with cancer, and this leads to changes in the production of gut microbial metabolites that can suppress CTL activity, promote inflammatory responses, and/or aid cancer growth. Decreased levels of CTL-promoting metabolites such as short-chain fatty acids, indole metabolites and polyamines but increased levels of CTL-suppressing metabolites, such as certain bile acids along with oncogenic metabolites, have been observed in patients with cancer. This review summarizes the altered production of major microbial metabolites in patients with cancer and discusses the impact of these changes on anti-cancer CTL responses.
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Affiliation(s)
- Chang H Kim
- Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109; Mary H. Weiser Food Allergy Center, Center for Gastrointestinal Research, and Rogel Center for Cancer Research, University of Michigan School of Medicine, Ann Arbor, MI 48109
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Chang Y, Liu Y, Zou Y, Ye RD. Recent Advances in Studies of Serum Amyloid A: Implications in Inflammation, Immunity and Tumor Metastasis. Int J Mol Sci 2025; 26:987. [PMID: 39940756 PMCID: PMC11817213 DOI: 10.3390/ijms26030987] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/19/2025] [Accepted: 01/22/2025] [Indexed: 02/16/2025] Open
Abstract
Research on serum amyloid A (SAA) has seen major advancement in recent years with combined approaches of structural analysis and genetically altered mice. Initially identified as an acute-phase reactant, SAA is now recognized as a major player in host defense, inflammation, lipid metabolism and tumor metastasis. SAA binding and the neutralization of LPS attenuate sepsis in mouse models. SAA also displays immunomodulatory functions in Th17 differentiation and macrophage polarization, contributing to a pro-metastatic tumor microenvironment. In spite of the progress, the regulatory mechanisms for these diverse functions of SAA remain unclear. This review provides a brief summary of recent advances in SAA research on immunity, inflammation, tumor microenvironment and in vivo models.
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Affiliation(s)
- Yixin Chang
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Yezhou Liu
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Yuanrui Zou
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Richard D. Ye
- Kobilka Institute of Innovative Drug Discovery, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
- The Chinese University of Hong Kong, Shenzhen Futian Biomedical Innovation R&D Center, Shenzhen 518000, China
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5
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Rajasekaran S, Cheng S, Gajendran N, Shekoohi S, Chesnokova L, Yu X, Witt SN. Transcriptomic analysis of melanoma cells reveals an association of α-synuclein with regulation of the inflammatory response. Sci Rep 2024; 14:27140. [PMID: 39511366 PMCID: PMC11544018 DOI: 10.1038/s41598-024-78777-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Accepted: 11/04/2024] [Indexed: 11/15/2024] Open
Abstract
The Parkinson's disease protein, alpha-synuclein (α-syn/SNCA), is highly expressed in neurons and melanomas. The goal of this study was to reveal the mechanism(s) of α-syn's involvement in melanoma pathogenesis. To decipher the genes and pathways affected by α-syn, we conducted an RNA sequencing analysis of human SK-MEL-28 cells and several SK-MEL-28 SNCA-KO clones. We identified 1098 significantly up-regulated genes and 660 significantly down-regulated genes. Several of the upregulated genes are related to the immune system, i.e., the inflammatory response and the matrisome. We validated five upregulated genes (IL-1β, SAA1, IGFBP5, CXCL8, and CXCL10) by RT-qPCR and detected IGFBP5 and IL-1β in spent media of control and SNCA-KO cells. The levels of each of these secreted proteins were significantly higher in the spent media of the SNCA-KO clones than control cells. These secreted proteins quite likely activate the immune response against SNCA-KO cells. We suggest that, conversely, high levels of α-syn expression in melanoma cells helps the cells evade the immune system by inhibiting the secretion of these immune activating factors.
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Affiliation(s)
- Santhanasabapathy Rajasekaran
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Siyuan Cheng
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Nithya Gajendran
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Sahar Shekoohi
- Department of Anesthesiology, Louisiana State University Health Sciences Center at Shreveport, 1501 Kings Highway, Shreveport, LA, 71103, USA
| | - Liudmila Chesnokova
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, USA
| | - Xiuping Yu
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, USA
- Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, USA
| | - Stephan N Witt
- Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, USA.
- Feist-Weiller Cancer Center, Louisiana State University Health Shreveport, Shreveport, USA.
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Voukali E, Divín D, Samblas MG, Veetil NK, Krajzingrová T, Těšický M, Li T, Melepat B, Talacko P, Vinkler M. Subclinical peripheral inflammation has systemic effects impacting central nervous system proteome in budgerigars. DEVELOPMENTAL AND COMPARATIVE IMMUNOLOGY 2024; 159:105213. [PMID: 38880215 DOI: 10.1016/j.dci.2024.105213] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/31/2024] [Revised: 06/13/2024] [Accepted: 06/13/2024] [Indexed: 06/18/2024]
Abstract
Regulation of neuroimmune interactions varies across avian species. Little is presently known about the interplay between periphery and central nervous system (CNS) in parrots, birds sensitive to neuroinflammation. Here we investigated the systemic and CNS responses to dextran sulphate sodium (DSS)- and lipopolysaccharide (LPS)-induced subclinical acute peripheral inflammation in budgerigar (Melopsittacus undulatus). Three experimental treatment groups differing in DSS and LPS stimulation were compared to controls. Individuals treated with DSS showed significant histological intestinal damage. Through quantitative proteomics we described changes in plasma (PL) and cerebrospinal fluid (CSF) composition. In total, we identified 180 proteins in PL and 978 proteins in CSF, with moderate co-structure between the proteomes. Between treatments we detected differences in immune, coagulation and metabolic pathways. Proteomic variation was associated with the levels of pro-inflammatory cytokine mRNA expression in intestine and brain. Our findings shed light on systemic impacts of peripheral low-grade inflammation in birds.
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Affiliation(s)
- Eleni Voukali
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic.
| | - Daniel Divín
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Mercedes Goméz Samblas
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Nithya Kuttiyarthu Veetil
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Tereza Krajzingrová
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Martin Těšický
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Tao Li
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Balraj Melepat
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic
| | - Pavel Talacko
- Biotechnology and Biomedicine Centre of Academy of Sciences and Charles University, Laboratory of OMICS Proteomics and Metabolomics, Průmyslová 595, 252 50, Vestec, Czech Republic
| | - Michal Vinkler
- Charles University, Faculty of Science, Department of Zoology, Viničná 7, 128 43, Prague, Czech Republic.
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Tang Y, Zhang Y, Zhang D, Liu Y, Nussinov R, Zheng J. Exploring pathological link between antimicrobial and amyloid peptides. Chem Soc Rev 2024; 53:8713-8763. [PMID: 39041297 DOI: 10.1039/d3cs00878a] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/24/2024]
Abstract
Amyloid peptides (AMYs) and antimicrobial peptides (AMPs) are considered as the two distinct families of peptides, characterized by their unique sequences, structures, biological functions, and specific pathological targets. However, accumulating evidence has revealed intriguing pathological connections between these peptide families in the context of microbial infection and neurodegenerative diseases. Some AMYs and AMPs share certain structural and functional characteristics, including the ability to self-assemble, the presence of β-sheet-rich structures, and membrane-disrupting mechanisms. These shared features enable AMYs to possess antimicrobial activity and AMPs to acquire amyloidogenic properties. Despite limited studies on AMYs-AMPs systems, the cross-seeding phenomenon between AMYs and AMPs has emerged as a crucial factor in the bidirectional communication between the pathogenesis of neurodegenerative diseases and host defense against microbial infections. In this review, we examine recent developments in the potential interplay between AMYs and AMPs, as well as their pathological implications for both infectious and neurodegenerative diseases. By discussing the current progress and challenges in this emerging field, this account aims to inspire further research and investments to enhance our understanding of the intricate molecular crosstalk between AMYs and AMPs. This knowledge holds great promise for the development of innovative therapies to combat both microbial infections and neurodegenerative disorders.
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Affiliation(s)
- Yijing Tang
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Ohio 44325, USA.
| | - Yanxian Zhang
- Division of Endocrinology and Diabetes, Department of Pediatrics, School of Medicine, Stanford University, Palo Alto, CA 94304, USA
| | - Dong Zhang
- The Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, Atlanta, Georgia 30332, USA
| | - Yonglan Liu
- Cancer Innovation Laboratory, National Cancer Institute, Frederick, MD 21702, USA
| | - Ruth Nussinov
- Computational Structural Biology Section, Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA.
- Department of Human Molecular Genetics and Biochemistry Sackler School of Medicine, Tel Aviv University, Tel Aviv 69978, Israel
| | - Jie Zheng
- Department of Chemical, Biomolecular, and Corrosion Engineering, The University of Akron, Ohio 44325, USA.
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Zindl CL, Wilson CG, Chadha AS, Duck LW, Cai B, Harbour SN, Nagaoka-Kamata Y, Hatton RD, Gao M, Figge DA, Weaver CT. Distal colonocytes targeted by C. rodentium recruit T-cell help for barrier defence. Nature 2024; 629:669-678. [PMID: 38600382 PMCID: PMC11096101 DOI: 10.1038/s41586-024-07288-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2023] [Accepted: 03/08/2024] [Indexed: 04/12/2024]
Abstract
Interleukin 22 (IL-22) has a non-redundant role in immune defence of the intestinal barrier1-3. T cells, but not innate lymphoid cells, have an indispensable role in sustaining the IL-22 signalling that is required for the protection of colonic crypts against invasion during infection by the enteropathogen Citrobacter rodentium4 (Cr). However, the intestinal epithelial cell (IEC) subsets targeted by T cell-derived IL-22, and how T cell-derived IL-22 sustains activation in IECs, remain undefined. Here we identify a subset of absorptive IECs in the mid-distal colon that are specifically targeted by Cr and are differentially responsive to IL-22 signalling. Major histocompatibility complex class II (MHCII) expression by these colonocytes was required to elicit sustained IL-22 signalling from Cr-specific T cells, which was required to restrain Cr invasion. Our findings explain the basis for the regionalization of the host response to Cr and demonstrate that epithelial cells must elicit MHCII-dependent help from IL-22-producing T cells to orchestrate immune protection in the intestine.
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Affiliation(s)
- Carlene L Zindl
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
| | - C Garrett Wilson
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Awalpreet S Chadha
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Lennard W Duck
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Baiyi Cai
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Stacey N Harbour
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Yoshiko Nagaoka-Kamata
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Robin D Hatton
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Min Gao
- Department of Medicine, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - David A Figge
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA
| | - Casey T Weaver
- Department of Pathology, Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA.
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Ait-Idir D, Djerdjouri B, Latreche K, Sari-Hamidou R, Khellaf G. Predicting genetic risk factors for AA amyloidosis in Algerian patients with familial Mediterranean fever. Mol Genet Genomics 2024; 299:25. [PMID: 38451362 DOI: 10.1007/s00438-024-02133-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2023] [Accepted: 02/22/2024] [Indexed: 03/08/2024]
Abstract
Renal amyloid-associated (AA) amyloidosis is a harmful complication of familial Mediterranean fever (FMF). Its occurrence involves polymorphisms and mutations in the Serum Amyloid A1 (SAA1) and Mediterranean Fever (MEFV) genes, respectively. In Algeria, the association between SAA1 variants and FMF-related amyloidosis was not investigated, hence the aim of this case-control study. It included 60 healthy controls and 60 unrelated FMF patients (39 with amyloidosis, and 21 without amyloidosis). All were genotyped for the SAA1 alleles (SAA1.1, SAA1.5, and SAA1.3), and a subset of them for the - 13 C/T polymorphism by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Comparisons between genotype and allele frequencies were performed using Chi-square and Fisher tests. The SAA1.1/1.1 genotype was predominant in amyloid FMF patients, compared to non-amyloid FMF patients (p = 0.001) and controls (p < 0.0001). SAA1.1/1.5 was higher in non-amyloid patients (p = 0.0069) and in controls (p = 0.0082) than in patients with amyloidosis. Bivariate logistic regression revealed an increased risk of AA amyloidosis with three genotypes, SAA1.1/1.1 [odds ratio 7.589 (OR); 95% confidence interval (CI): 2.130-27.041] (p = 0.0018), SAA1.1/1.3 [OR 5.700; 95% CI: 1.435-22.644] (p = 0.0134), and M694I/M694I [OR 4.6; 95% CI: 1.400-15.117] (p = 0.0119). The SAA1.1/1.5 genotype [OR 0.152; 95% CI: 0.040-0.587] (p = 0.0062) was protective against amyloidosis. In all groups, the - 13 C/C genotype predominated, and was not related to renal complication [OR 0.88; 95% CI: 0.07-10.43] (p = 0.915). In conclusion, in contrast to the - 13 C/T polymorphism, the SAA1.1/1.1, SAA1.1/1.3 and M694I/M694I genotypes may increase the risk of developing renal AA amyloidosis in the Algerian population.
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Affiliation(s)
- Djouher Ait-Idir
- Research Laboratory, Biodiversity, Biotechnology, Environment and Sustainable Development, Department of Biology, Faculty of Sciences, M'Hamed Bougara University, Boumerdes, Algeria.
| | - Bahia Djerdjouri
- Tamayouz Laboratory of Cellular and Molecular Biology, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | - Khaled Latreche
- Department of Biology, Faculty of Sciences, M'Hamed Bougara University, Boumerdes, Algeria
- Research Laboratory on Arid Regions, Faculty of Biological Sciences, University of Sciences and Technology Houari Boumediene, Algiers, Algeria
| | - Rawda Sari-Hamidou
- Department of Nephrology, Tidjani Damerdji University Hospital, Tlemcen, Algeria
- Research laboratory Toxicomed, Faculty of Medicine, Abou-Bekr Belkaid Tlemcen University, Tlemcen, Algeria
| | - Ghalia Khellaf
- Faculty of Medecine, Benyoucef Benkheda Algiers 1 University, Algiers, Algeria
- Department of Nephrology, Mohamed Lamine Debaghine University Hospital, Algiers, Algeria
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Li M, Kim YM, Koh JH, Park J, Kwon HM, Park JH, Jin J, Park Y, Kim D, Kim WU. Serum amyloid A expression in liver promotes synovial macrophage activation and chronic arthritis via NFAT5. J Clin Invest 2024; 134:e167835. [PMID: 38426494 PMCID: PMC10904059 DOI: 10.1172/jci167835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/05/2024] [Indexed: 03/02/2024] Open
Abstract
Nuclear factor of activated T-cells 5 (NFAT5), an osmo-sensitive transcription factor, can be activated by isotonic stimuli, such as infection. It remains unclear, however, whether NFAT5 is required for damage-associated molecular pattern-triggered (DAMP-triggered) inflammation and immunity. Here, we found that several DAMPs increased NFAT5 expression in macrophages. In particular, serum amyloid A (SAA), primarily generated by the liver, substantially upregulated NFAT5 expression and activity through TLR2/4-JNK signalling pathway. Moreover, the SAA-TLR2/4-NFAT5 axis promoted migration and chemotaxis of macrophages in an IL-6- and chemokine ligand 2-dependent (CCL2-dependent) manner in vitro. Intraarticular injection of SAA markedly accelerated macrophage infiltration and arthritis progression in mice. By contrast, genetic ablation of NFAT5 or TLR2/4 rescued the pathology induced by SAA, confirming the SAA-TLR2/4-NFAT5 axis in vivo. Myeloid-specific depletion of NFAT5 also attenuated SAA-accelerated arthritis. Of note, inflammatory arthritis in mice strikingly induced SAA overexpression in the liver. Conversely, forced overexpression of the SAA gene in the liver accelerated joint damage, indicating that the liver contributes to bolstering chronic inflammation at remote sites by secreting SAA. Collectively, this study underscores the importance of the SAA-TLR2/4-NFAT5 axis in innate immunity, suggesting that acute phase reactant SAA mediates mutual interactions between liver and joints and ultimately aggravates chronic arthritis by enhancing macrophage activation.
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Affiliation(s)
- Meiling Li
- Center for Integrative Rheumatoid Transcriptomics and Dynamics
- Department of Biomedicine and Health Sciences, and
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Yu-Mi Kim
- Center for Integrative Rheumatoid Transcriptomics and Dynamics
- Department of Biomedicine and Health Sciences, and
| | - Jung Hee Koh
- Division of Rheumatology, Department of Internal Medicine, Uijeoungbu St.Mary’s hospital, the Catholic University of Korea, Uijeoungbu, Republic of Korea
| | - Jihyun Park
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
| | - H. Moo Kwon
- School of Nano-Bioscience and Chemical Engineering, Ulsan National Institute of Science and Technology, Ulsan, Republic of Korea
| | - Jong-Hwan Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Chonnam National University, Gwangju, Republic of Korea
| | - Jingchun Jin
- Department of Immunology of Yanbian University Hospital, Yanji, Jilin Province, China
- Key Laboratory of Science and Technology Department (Jilin Province), Cancer Research Center, Yanji, Jilin Province, China
| | - Youngjae Park
- Department of Biomedicine and Health Sciences, and
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Donghyun Kim
- Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul, Republic of Korea
- Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, Republic of Korea
- Institute of Endemic Diseases, Seoul National University Medical Research Center, Seoul, Republic of Korea
| | - Wan-Uk Kim
- Center for Integrative Rheumatoid Transcriptomics and Dynamics
- Department of Biomedicine and Health Sciences, and
- Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
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11
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Ji A, Trumbauer AC, Noffsinger VP, Meredith LW, Dong B, Wang Q, Guo L, Li X, De Beer FC, Webb NR, Tannock LR, Starr ME, Waters CM, Shridas P. Deficiency of Acute-Phase Serum Amyloid A Exacerbates Sepsis-Induced Mortality and Lung Injury in Mice. Int J Mol Sci 2023; 24:17501. [PMID: 38139330 PMCID: PMC10744229 DOI: 10.3390/ijms242417501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2023] [Revised: 12/11/2023] [Accepted: 12/13/2023] [Indexed: 12/24/2023] Open
Abstract
Serum amyloid A (SAA) is a family of proteins, the plasma levels of which may increase >1000-fold in acute inflammatory states. We investigated the role of SAA in sepsis using mice deficient in all three acute-phase SAA isoforms (SAA-TKO). SAA deficiency significantly increased mortality rates in the three experimental sepsis mouse models: cecal ligation and puncture (CLP), cecal slurry (CS) injection, and lipopolysaccharide (LPS) treatments. SAA-TKO mice had exacerbated lung pathology compared to wild-type (WT) mice after CLP. A bulk RNA sequencing performed on lung tissues excised 24 h after CLP indicated significant enrichment in the expression of genes associated with chemokine production, chemokine and cytokine-mediated signaling, neutrophil chemotaxis, and neutrophil migration in SAA-TKO compared to WT mice. Consistently, myeloperoxidase activity and neutrophil counts were significantly increased in the lungs of septic SAA-TKO mice compared to WT mice. The in vitro treatment of HL-60, neutrophil-like cells, with SAA or SAA bound to a high-density lipoprotein (SAA-HDL), significantly decreased cellular transmigration through laminin-coated membranes compared to untreated cells. Thus, SAA potentially prevents neutrophil transmigration into injured lungs, thus reducing exacerbated tissue injury and mortality. In conclusion, we demonstrate for the first time that endogenous SAA plays a protective role in sepsis, including ameliorating lung injury.
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Affiliation(s)
- Ailing Ji
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
| | - Andrea C. Trumbauer
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
| | - Victoria P. Noffsinger
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
| | - Luke W. Meredith
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
| | - Brittany Dong
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; (B.D.); (C.M.W.)
| | - Qian Wang
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
| | - Ling Guo
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
| | - Xiangan Li
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; (B.D.); (C.M.W.)
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA;
| | - Frederick C. De Beer
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA;
| | - Nancy R. Webb
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA;
| | - Lisa R. Tannock
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA;
| | - Marlene E. Starr
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA;
- Department of Surgery, College of Medicine, University of Kentucky, Lexington, KY 40536, USA
| | - Christopher M. Waters
- Department of Physiology, University of Kentucky, Lexington, KY 40536, USA; (B.D.); (C.M.W.)
| | - Preetha Shridas
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA; (A.J.); (A.C.T.); (V.P.N.); (L.W.M.); (Q.W.); (L.G.); (X.L.); (N.R.W.); (L.R.T.)
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA;
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12
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Winkler R, Lu H. Cell-Specific Regulation of Inflammatory Cytokines and Acute-Phase Proteins by the Glucocorticoid Receptor. Mediators Inflamm 2023; 2023:4399998. [PMID: 39619227 PMCID: PMC11606692 DOI: 10.1155/2023/4399998] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 09/08/2023] [Accepted: 10/24/2023] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Literature and data mining found abnormal induction of chemokine (C-X-C motif) ligand 1 (CXCL1) and CXCL8 and down-regulation of CXCL2 in inflammatory liver diseases. This study was performed to understand the glucocorticoid receptor's (GR's) effects on chemokine and acute-phase protein expression in human liver, in settings of bacterial infection (modeled using LPS) or inflammation (modeled using TNFα). METHODS Primary human hepatocytes (PHH) were treated with combinations of tumor necrosis factor alpha (TNFα), lipopolysaccharide (LPS), and dexamethasone (DEX) for 24 h, following which chemokine mRNA and protein expression were analyzed using qPCR and enzyme-linked immunosorbent assay assays. Dual luciferase assays were performed on transfected cell lines. Mutant CXCL2 promoters were used in dual luciferase assays to identify specific regions of the CXCL2 promoter affected by GR, TNFα, or hepatocyte nuclear factor 4α (HNF4α, a liver-enriched transcription factor). RESULTS In PHH from donor 1, GR strongly inhibited LPS-induced CXCL1 and CXCL8 translation and transcription, whereas CXCL2 transcription tended to increase with DEX treatment. In PHH from donor 2, DEX treatment inhibited protein expression and secretion of CXCL1 and CXCL8 induced by TNFα and/or LPS, whereas CXCL2 upregulation was largely unaffected by DEX treatment. In nonliver HEK293T cells GR activity inhibited CXCL2 promoter activity. However, in liver-derived HEPG2 cells, GR induced CXCL2 promoter activity. A 407-base pair region upstream of CXCL2 promoter is necessary for full GR functionality in HEPG2 cells. TNFα synergized with HNF4α in inducing CXCL2 promoter activity in HEPG2 cells. CONCLUSIONS GR's effects on chemokine expression are cell-type specific and chemokine specific. GR down-regulated CXCL1 and CXCL8 in different cell types, whereas the specific activation of CXCL2 in hepatocytes and down-regulation of CXCL2 in nonhepatocytes by GR appears due to cell-specific utilization of CXCL2 promoter. By specifically increasing GR activity in the liver, we may normalize chemokine imbalances and prevent sepsis in inflammatory liver diseases.
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Affiliation(s)
- Rebecca Winkler
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
| | - Hong Lu
- Department of Pharmacology, SUNY Upstate Medical University, Syracuse, NY 13210, USA
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13
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Li J, Simmons AJ, Chiron S, Ramirez-Solano MA, Tasneem N, Kaur H, Xu Y, Revetta F, Vega PN, Bao S, Cui C, Tyree RN, Raber LW, Conner AN, Beaulieu DB, Dalal RL, Horst SN, Pabla BS, Huo Y, Landman BA, Roland JT, Scoville EA, Schwartz DA, Washington MK, Shyr Y, Wilson KT, Coburn LA, Lau KS, Liu Q. A Specialized Epithelial Cell Type Regulating Mucosal Immunity and Driving Human Crohn's Disease. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.30.560293. [PMID: 37873404 PMCID: PMC10592875 DOI: 10.1101/2023.09.30.560293] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/25/2023]
Abstract
Crohn's disease (CD) is a complex chronic inflammatory disorder that may affect any part of gastrointestinal tract with extra-intestinal manifestations and associated immune dysregulation. To characterize heterogeneity in CD, we profiled single-cell transcriptomics of 170 samples from 65 CD patients and 18 non-inflammatory bowel disease (IBD) controls in both the terminal ileum (TI) and ascending colon (AC). Analysis of 202,359 cells identified a novel epithelial cell type in both TI and AC, featuring high expression of LCN2, NOS2, and DUOX2, and thus is named LND. LND cells, confirmed by high-resolution in-situ RNA imaging, were rarely found in non-IBD controls, but expanded significantly in active CD. Compared to other epithelial cells, genes defining LND cells were enriched in antimicrobial response and immunoregulation. Moreover, multiplexed protein imaging demonstrated that LND cell abundance was associated with immune infiltration. Cross-talk between LND and immune cells was explored by ligand-receptor interactions and further evidenced by their spatial colocalization. LND cells showed significant enrichment of expression specificity of IBD/CD susceptibility genes, revealing its role in immunopathogenesis of CD. Investigating lineage relationships of epithelial cells detected two LND cell subpopulations with different origins and developmental potential, early and late LND. The ratio of the late to early LND cells was related to anti-TNF response. These findings emphasize the pathogenic role of the specialized LND cell type in both Crohn's ileitis and Crohn's colitis and identify novel biomarkers associated with disease activity and treatment response.
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Affiliation(s)
- Jia Li
- Center for Quantitative Sciences, Vanderbilt Univerity Medical Center, Nashville, TN, USA
- Department of Biostatistics, Vanderbilt Univerity Medical Center, Nashville, TN, USA
| | - Alan J. Simmons
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Sophie Chiron
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Marisol A. Ramirez-Solano
- Center for Quantitative Sciences, Vanderbilt Univerity Medical Center, Nashville, TN, USA
- Department of Biostatistics, Vanderbilt Univerity Medical Center, Nashville, TN, USA
| | - Naila Tasneem
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Harsimran Kaur
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Yanwen Xu
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Frank Revetta
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Paige N. Vega
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
| | - Shunxing Bao
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
- Department of Computer Science, Vanderbilt University, Nashville, TN, USA
| | - Can Cui
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
- Department of Computer Science, Vanderbilt University, Nashville, TN, USA
| | - Regina N. Tyree
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Larry W. Raber
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Anna N. Conner
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Dawn B. Beaulieu
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Robin L. Dalal
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Sara N. Horst
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Baldeep S. Pabla
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - Yuankai Huo
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
- Department of Computer Science, Vanderbilt University, Nashville, TN, USA
| | - Bennett A. Landman
- Department of Electrical and Computer Engineering, Vanderbilt University, Nashville, TN, USA
- Department of Computer Science, Vanderbilt University, Nashville, TN, USA
| | - Joseph T. Roland
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville TN, USA
| | - Elizabeth A. Scoville
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - David A. Schwartz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
| | - M. Kay Washington
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Yu Shyr
- Center for Quantitative Sciences, Vanderbilt Univerity Medical Center, Nashville, TN, USA
- Department of Biostatistics, Vanderbilt Univerity Medical Center, Nashville, TN, USA
| | - Keith T. Wilson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Lori A. Coburn
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
- Veterans Affairs Tennessee Valley Healthcare System, Nashville, TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Ken S. Lau
- Center for Quantitative Sciences, Vanderbilt Univerity Medical Center, Nashville, TN, USA
- Epithelial Biology Center, Vanderbilt University Medical Center, Nashville, TN, USA
- Department of Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Program in Chemical and Physical Biology, Vanderbilt University School of Medicine, Nashville, TN, USA
- Department of Surgery, Vanderbilt University Medical Center, Nashville TN, USA
- Center for Mucosal Inflammation and Cancer, Vanderbilt University Medical Center; Nashville, TN, USA
| | - Qi Liu
- Center for Quantitative Sciences, Vanderbilt Univerity Medical Center, Nashville, TN, USA
- Department of Biostatistics, Vanderbilt Univerity Medical Center, Nashville, TN, USA
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14
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Vermeersch AS, Ali M, Gansemans Y, Van Nieuwerburgh F, Geldhof P, Ducatelle R, Deforce D, Callens J, Opsomer G. Severe udder cleft dermatitis lesion transcriptomics points to an impaired skin barrier, defective wound repair and a dysregulated inflammatory response as key elements in the pathogenesis. PLoS One 2023; 18:e0288347. [PMID: 37486897 PMCID: PMC10365316 DOI: 10.1371/journal.pone.0288347] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2023] [Accepted: 06/20/2023] [Indexed: 07/26/2023] Open
Abstract
This study is the first to investigate the transcriptomic changes occurring in severe udder cleft dermatitis lesions (UCD) in Holstein-Friesian cows. An examination of the gene expression levels in natural UCD lesions and healthy udder skin through RNA Seq-Technology provided a deeper insight into the inflammatory pathways associated with this disease. A clear distinction between the gene expression patterns of UCD lesions and healthy skin was shown in the principal component analysis. Genes coding for inflammatory molecules were upregulated such as the chemokines C-X-C motif ligand 2 (CXCL2), 5 (CXCL5) and 8 (CXCL8), and C-C motif ligand 11 (CCL11). Moreover, the genes coding for the multifunctional molecules ADAM12 and SLPI were amongst the highest upregulated ones, whereas the most downregulated genes included the ones coding for keratins and keratin-associated molecules. Predominantly inflammatory pathways such as the chemokine signaling, cytokine receptor interaction and IL-17 signaling pathway were significantly upregulated in the pathway analysis. These results point towards a fulminant, dysregulated inflammatory response concomitant with a disruption of the skin barrier integrity and a hampered wound repair mechanism in severe UCD lesions.
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Affiliation(s)
- A S Vermeersch
- Department of Internal Medicine, Reproduction and Population Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - M Ali
- Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - Y Gansemans
- Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - F Van Nieuwerburgh
- Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - P Geldhof
- Department of Translational Physiology, Infectiology and Public Health, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - R Ducatelle
- Department of Pathobiology, Pharmacology and Zoological Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - D Deforce
- Laboratory of Pharmaceutical Biotechnology, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium
| | - J Callens
- Dierengezondheidszorg Vlaanderen, Torhout, Belgium
| | - G Opsomer
- Department of Internal Medicine, Reproduction and Population Medicine, Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
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15
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den Hartigh LJ, May KS, Zhang XS, Chait A, Blaser MJ. Serum amyloid A and metabolic disease: evidence for a critical role in chronic inflammatory conditions. Front Cardiovasc Med 2023; 10:1197432. [PMID: 37396595 PMCID: PMC10311072 DOI: 10.3389/fcvm.2023.1197432] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2023] [Accepted: 05/15/2023] [Indexed: 07/04/2023] Open
Abstract
Serum amyloid A (SAA) subtypes 1-3 are well-described acute phase reactants that are elevated in acute inflammatory conditions such as infection, tissue injury, and trauma, while SAA4 is constitutively expressed. SAA subtypes also have been implicated as playing roles in chronic metabolic diseases including obesity, diabetes, and cardiovascular disease, and possibly in autoimmune diseases such as systemic lupus erythematosis, rheumatoid arthritis, and inflammatory bowel disease. Distinctions between the expression kinetics of SAA in acute inflammatory responses and chronic disease states suggest the potential for differentiating SAA functions. Although circulating SAA levels can rise up to 1,000-fold during an acute inflammatory event, elevations are more modest (∼5-fold) in chronic metabolic conditions. The majority of acute-phase SAA derives from the liver, while in chronic inflammatory conditions SAA also derives from adipose tissue, the intestine, and elsewhere. In this review, roles for SAA subtypes in chronic metabolic disease states are contrasted to current knowledge about acute phase SAA. Investigations show distinct differences between SAA expression and function in human and animal models of metabolic disease, as well as sexual dimorphism of SAA subtype responses.
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Affiliation(s)
- Laura J. den Hartigh
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
| | - Karolline S. May
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
| | - Xue-Song Zhang
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, United States
| | - Alan Chait
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition, University of Washington, Seattle, WA, United States
- Diabetes Institute, University of Washington, Seattle, WA, United States
| | - Martin J. Blaser
- Center for Advanced Biotechnology and Medicine, Rutgers University, Piscataway, NJ, United States
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16
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Chen R, Chen Q, Zheng J, Zeng Z, Chen M, Li L, Zhang S. Serum amyloid protein A in inflammatory bowel disease: from bench to bedside. Cell Death Discov 2023; 9:154. [PMID: 37164984 PMCID: PMC10172326 DOI: 10.1038/s41420-023-01455-5] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 04/18/2023] [Accepted: 04/27/2023] [Indexed: 05/12/2023] Open
Abstract
Inflammatory bowel diseases (IBD) is featured by gastrointestinal inflammation and a disease course with alternating recurrence and remission. The global burden caused by IBD has significantly boosted in recent years, necessitating treatment optimization. Serum amyloid A (SAA) is a class of 104 amino acid conservative acute-phase proteins, which is essential in immune-mediated inflammatory processes, like IBD. The SAA monomeric structure is composed of four α-helical regions and a C-terminal amorphous tail. Its disordered structure enables multiple bindings to different ligands and permits multiple functions. It has been proven that SAA has dual roles in the inflammatory process. SAA stimulates the pro-inflammatory cytokine expression and promotes the pathogenic differentiation of TH17 cells. In addition, SAA can remove toxic lipids produced during inflammatory responses and membrane debris from dead cells, redirect HDL, and recycle cholesterol for tissue repair. In IBD, SAA acts on gut epithelium barriers, induces T-cell differentiation, and promotes phagocytosis of Gram-negative bacteria. Owing to the tight connection between SAA and IBD, several clinical studies have taken SAA for a biomarker for diagnosis, assessing disease activity, and predicting prognosis in IBD. Furthermore, 5-MER peptide, a drug specifically targeting SAA, has shown anti-inflammatory effects in some SAA-dependent animal models, providing novel insights into the therapeutic targets of IBD.
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Affiliation(s)
- Rirong Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Qia Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Jieqi Zheng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
- Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, China
| | - Zhirong Zeng
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Minhu Chen
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China
| | - Li Li
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
| | - Shenghong Zhang
- Department of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
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17
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Ji A, Trumbauer AC, Noffsinger VP, de Beer FC, Webb NR, Tannock LR, Shridas P. Serum amyloid A augments the atherogenic effects of cholesteryl ester transfer protein. J Lipid Res 2023; 64:100365. [PMID: 37004910 PMCID: PMC10165456 DOI: 10.1016/j.jlr.2023.100365] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Revised: 03/24/2023] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Serum amyloid A (SAA) is predictive of CVD in humans and causes atherosclerosis in mice. SAA has many proatherogenic effects in vitro. However, HDL, the major carrier of SAA in the circulation, masks these effects. The remodeling of HDL by cholesteryl ester transfer protein (CETP) liberates SAA restoring its proinflammatory activity. Here, we investigated whether deficiency of SAA suppresses the previously described proatherogenic effect of CETP. ApoE-/- mice and apoE-/- mice deficient in the three acute-phase isoforms of SAA (SAA1.1, SAA2.1, and SAA3; "apoE-/- SAA-TKO") with and without adeno-associated virus-mediated expression of CETP were studied. There was no effect of CETP expression or SAA genotype on plasma lipids or inflammatory markers. Atherosclerotic lesion area in the aortic arch of apoE-/- mice was 5.9 ± 1.2%; CETP expression significantly increased atherosclerosis in apoE-/- mice (13.1 ± 2.2%). However, atherosclerotic lesion area in the aortic arch of apoE-/- SAA-TKO mice (5.1 ± 1.1%) was not significantly increased by CETP expression (6.2 ± 0.9%). The increased atherosclerosis in apoE-/- mice expressing CETP was associated with markedly increased SAA immunostaining in aortic root sections. Thus, SAA augments the atherogenic effects of CETP, which suggests that inhibiting CETP may be of particular benefit in patients with high SAA.
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Affiliation(s)
- Ailing Ji
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Andrea C Trumbauer
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Victoria P Noffsinger
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA
| | - Frederick C de Beer
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA; Department of Internal Medicine, University of Kentucky, Lexington, KY, USA
| | - Nancy R Webb
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA; Department of Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY, USA
| | - Lisa R Tannock
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA; Department of Internal Medicine, University of Kentucky, Lexington, KY, USA; Lexington Veterans Affairs Medical Center, Lexington, KY, USA
| | - Preetha Shridas
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY, USA; Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY, USA; Department of Internal Medicine, University of Kentucky, Lexington, KY, USA.
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18
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Xu Z, Wu Y, Fu G, Chen X, Sun J, Tian J, Jiang P, Wang Y, Jin B. SAA1 Has Potential as a Prognostic Biomarker Correlated with Cell Proliferation, Migration, and an Indicator for Immune Infiltration of Tumor Microenvironment in Clear Cell Renal Cell Carcinoma. Int J Mol Sci 2023; 24:ijms24087505. [PMID: 37108666 PMCID: PMC10138873 DOI: 10.3390/ijms24087505] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2023] [Revised: 04/11/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
The tumor microenvironment (TME) plays an important part in the initiation and development of clear cell renal cell carcinoma (ccRCC). However, an understanding of the immune infiltration in TME is still unknown. Our study aims to explore the correlation between the TME and the clinical features, as well as the prognosis of ccRCC. In the present study, ESTIMATE and CIBERSORT computational methods were applied to calculate the proportion of tumor-infiltrating immune cells (TICs) and the amount of immune and stromal fractions in the ccRCC form The Cancer Genome Atlas (TCGA) database. Then, we sought to find out those immune cell types and genes which may play a significant role and validated them in the GEO database. Furthermore, an immunohistochemical analysis of our external validation dataset was used to detect SAA1 and PDL1 expression in the ccRCC cancer tissues and corresponding normal tissues. Statistical analysis was performed to study the relationship between SAA1 and clinical characteristics, as well as PDL1 expression. Furthermore, a ccRCC cell model with SAA1 knockdown was constructed, which was used for cell proliferation and the migration test. The intersection analysis of the univariate COX and PPI analysis were performed to imply Serum Amyloid A1 (SAA1) as a predictive factor. The expression of SAA1 was significantly negatively correlated to OS and positively correlated to the clinical TMN stage system. The genes in the high-expression SAA1 group were basically enriched in immune-related activities. The proportion of mast cells resting was negatively correlated with SAA1 expression, indicating that SAA1 may be involved in the maintenance of the immune status for the TME. Moreover, the PDL1 expression was positively related to the SAA1 expression and negatively correlated with the patients' prognosis. Further experiments revealed that the knockdown of SAA1 inhibited ccRCC development through suppressing cell proliferation and migration. SAA1 may be a novel marker for the prognosis prediction of ccRCC patients and may play a vital role in the TME by mast cell resting and PDL1 expression. SAA1 has the potential to become a therapeutic target and indicator for immune target therapy in ccRCC treatment.
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Affiliation(s)
- Zhijie Xu
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Yunfei Wu
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Guanghou Fu
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Xiaoyi Chen
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Junjie Sun
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Junjie Tian
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Peng Jiang
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Yimin Wang
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
| | - Baiye Jin
- Department of Urology, School of Medicine, The First Affiliated Hospital, Zhejiang University, Hangzhou 310009, China
- Zhejiang Engineering Research Center for Urinary Bladder Carcinoma Innovation Diagnosis and Treatment, Hangzhou 310024, China
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Lin YK, Zhang F, Lei WJ, Gan XW, Li MD, Pan F, Wang WS, Sun K. Amnion-derived serum amyloid A1 participates in sterile inflammation of fetal membranes at parturition. Inflamm Res 2023; 72:797-812. [PMID: 36879064 DOI: 10.1007/s00011-023-01713-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 02/05/2023] [Accepted: 02/19/2023] [Indexed: 03/08/2023] Open
Abstract
OBJECTIVES Sterile inflammation of fetal membranes is an indispensable event of normal parturition. However, triggers of sterile inflammation are not fully resolved. Serum amyloid A1 (SAA1) is an acute phase protein produced primarily by the liver. Fetal membranes can also synthesize SAA1 but its functions are not well defined. Given the role of SAA1 in the acute phase response to inflammation, we postulated that SAA1 synthesized in the fetal membranes may be a trigger of local inflammation at parturition. METHODS The changes of SAA1 abundance in parturition were studied in the amnion of human fetal membranes. The role of SAA1 in chemokine expression and leukocyte chemotaxis was examined in cultured human amnion tissue explants as well as primary human amnion fibroblasts. The effects of SAA1 on monocytes, macrophages and dendritic cells were investigated in cells derived from a human leukemia monocytic cell line (THP-1). RESULTS SAA1 synthesis increased significantly in human amnion at parturition. SAA1 evoked multiple chemotaxis pathways in human amnion fibroblasts along with upregulation of a series of chemokines via both toll-like receptor 4 (TLR4) and formyl peptide receptor 2 (FPR2). Moreover, SAA1-conditioned medium of cultured amnion fibroblasts was capable of chemoattracting virtually all types of mononuclear leukocytes, particularly monocytes and dendritic cells, which reconciled with the chemotactic activity of conditioned medium of cultured amnion tissue explants collected from spontaneous labor. Furthermore, SAA1 could induce the expression of genes associated with inflammation and extracellular matrix remodeling in monocytes, macrophages and dendritic cells derived from THP-1. CONCLUSIONS SAA1 is a trigger of sterile inflammation of the fetal membranes at parturition.
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Affiliation(s)
- Yi-Kai Lin
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
| | - Fan Zhang
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
| | - Wen-Jia Lei
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
| | - Xiao-Wen Gan
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
| | - Meng-Die Li
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
| | - Fan Pan
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China.,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China
| | - Wang-Sheng Wang
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China. .,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China.
| | - Kang Sun
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong university, Shanghai, People's Republic of China. .,Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, People's Republic of China.
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20
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You K, Wang Y, Chen X, Yang Z, Chen Y, Tan S, Tao J, Getachew A, Pan T, Xu Y, Zhuang Y, Yang F, Lin X, Li Y. Neutralizing serum amyloid a protects against sinusoidal endothelial cell damage and platelet aggregation during acetaminophen-induced liver injury. Biochem Biophys Res Commun 2023; 639:20-28. [PMID: 36463757 DOI: 10.1016/j.bbrc.2022.11.079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Revised: 11/08/2022] [Accepted: 11/25/2022] [Indexed: 11/29/2022]
Abstract
Serum amyloid A (SAA) is an acute response protein that mainly produced by hepatocytes, and it can promote endothelial dysfunction via a pro-inflammatory and pro-thrombotic effect in atherosclerosis and renal disease. Overdose of Acetaminophen (APAP) will cause hepatotoxicity accompany with hepatocyte necrosis, liver sinusoidal endothelial cells (LSECs) damage and thrombosis in liver. However, whether SAA plays a role in APAP-induced liver toxicity remains unclear. Here, we evaluated the Saa1/2 expression in APAP-induced liver injury, and found that Saa1/2 production was significantly increased in an autocrine manner in APAP injury model. Moreover, we used neutralizing antibody (anti-SAA) to block the function of serum Saa1/2. We found that neutralizing serum Saa1/2 protected against APAP-induced liver injuries and increased the survival rate of mice that were treated with lethal dose APAP. Further investigations showed that blocking Saa1/2 reduced APAP-induced sinusoidal endothelium damage, hemorrhage and thrombosis. In addition, in vitro experiments showed that Saa1/2 augmented the toxic effect of APAP on LSECs, and Saa1/2 promoted platelets aggregation on LSECs cell membrane. Taken together, this study suggests that Saa1/2 may play a critical role in APAP-induced liver damages through platelets aggregation and sinusoidal damage. Therefore, we conceptually demonstrate that inhibition of SAA may be a potential intervention for APAP-directed acute liver injuries.
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Affiliation(s)
- Kai You
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China.
| | - Yan Wang
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xiaoxia Chen
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Zhen Yang
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China
| | - Yan Chen
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Shenglin Tan
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China
| | - Jiawang Tao
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Anteneh Getachew
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Tingcai Pan
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yingying Xu
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yuanqi Zhuang
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Fan Yang
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Xianhua Lin
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China
| | - Yinxiong Li
- Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, China; University of Chinese Academy of Sciences, Beijing, China; Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou, China; Bioland Laboratory (Guangzhou Regenerative Medicine and Health Guangdong Laboratory), Guangzhou, China.
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21
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Abouelasrar Salama S, Gouwy M, Van Damme J, Struyf S. Acute-serum amyloid A and A-SAA-derived peptides as formyl peptide receptor (FPR) 2 ligands. Front Endocrinol (Lausanne) 2023; 14:1119227. [PMID: 36817589 PMCID: PMC9935590 DOI: 10.3389/fendo.2023.1119227] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2022] [Accepted: 01/23/2023] [Indexed: 02/05/2023] Open
Abstract
Originally, it was thought that a single serum amyloid A (SAA) protein was involved in amyloid A amyloidosis, but in fact, SAA represents a four-membered family wherein SAA1 and SAA2 are acute phase proteins (A-SAA). SAA is highly conserved throughout evolution within a wide range of animal species suggestive of an important biological function. In fact, A-SAA has been linked to a number of divergent biological activities wherein a number of these functions are mediated via the G protein-coupled receptor (GPCR), formyl peptide receptor (FPR) 2. For instance, through the activation of FPR2, A-SAA has been described to regulate leukocyte activation, atherosclerosis, pathogen recognition, bone formation and cell survival. Moreover, A-SAA is subject to post-translational modification, primarily through proteolytic processing, generating a range of A-SAA-derived peptides. Although very little is known regarding the biological effect of A-SAA-derived peptides, they have been shown to promote neutrophil and monocyte migration through FPR2 activation via synergy with other GPCR ligands namely, the chemokines CXCL8 and CCL3, respectively. Within this review, we provide a detailed analysis of the FPR2-mediated functions of A-SAA. Moreover, we discuss the potential role of A-SAA-derived peptides as allosteric modulators of FPR2.
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22
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Fosheim IK, Jacobsen DP, Sugulle M, Alnaes-Katjavivi P, Fjeldstad HES, Ueland T, Lekva T, Staff AC. Serum amyloid A1 and pregnancy zone protein in pregnancy complications and correlation with markers of placental dysfunction. Am J Obstet Gynecol MFM 2023; 5:100794. [PMID: 36334725 DOI: 10.1016/j.ajogmf.2022.100794] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 10/06/2022] [Accepted: 10/28/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND Hypertensive disorders of pregnancy (preeclampsia, gestational hypertension, and chronic hypertension), diabetes mellitus, and placental dysfunction confer an increased risk of long-term maternal cardiovascular disease. Preeclampsia is also associated with acute atherosis that involves lesions of uteroplacental spiral arteries, resembling early stages of atherosclerosis. Serum amyloid A1 is involved in hypercoagulability and atherosclerosis and may aggregate into amyloid-aggregations of misfolded proteins. Pregnancy zone protein may inhibit amyloid aggregation. Amyloid is involved in Alzheimer's disease and cardiovascular disease; it has been identified in preeclampsia, but its role in preeclampsia pathophysiology is unclear. OBJECTIVE We hypothesized that serum amyloid A1 would be increased and pregnancy zone protein decreased in hypertensive disorders of pregnancy and diabetic pregnancies and that serum amyloid A1 and pregnancy zone protein would correlate with placental dysfunction markers (fetal growth restriction and dysregulated angiogenic biomarkers) and acute atherosis. STUDY DESIGN Serum amyloid A1 is measurable in both the serum and plasma. In our study, plasma from 549 pregnancies (normotensive, euglycemic controls: 258; early-onset preeclampsia: 71; late-onset preeclampsia: 98; gestational hypertension: 30; chronic hypertension: 9; diabetes mellitus: 83) was assayed for serum amyloid A1 and pregnancy zone protein. The serum levels of angiogenic biomarkers soluble fms-like tyrosine kinase-1 and placental growth factor were available for 547 pregnancies, and the results of acute atherosis evaluation were available for 313 pregnancies. The clinical characteristics and circulating biomarkers were compared between the pregnancy groups using the Mann-Whitney U, chi-squared, or Fisher exact test as appropriate. Spearman's rho was calculated for assessing correlations. RESULTS In early-onset preeclampsia, serum amyloid A1 was increased compared with controls (17.1 vs 5.1 µg/mL, P<.001), whereas pregnancy zone protein was decreased (590 vs 892 µg/mL, P=.002). Pregnancy zone protein was also decreased in diabetes compared with controls (683 vs 892 µg/mL, P=.01). Serum amyloid A1 was associated with placental dysfunction (fetal growth restriction, elevated soluble fms-like tyrosine kinase-1 to placental growth factor ratio). Pregnancy zone protein correlated negatively with soluble fms-like tyrosine kinase-1 to placental growth factor ratio in all study groups. Acute atherosis was not associated with serum amyloid A1 or pregnancy zone protein. CONCLUSION Proteins involved in atherosclerosis, hypercoagulability, and protein misfolding are dysregulated in early-onset preeclampsia and placental dysfunction, which links them and potentially contributes to future maternal cardiovascular disease.
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Affiliation(s)
- Ingrid K Fosheim
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff).
| | - Daniel P Jacobsen
- Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff)
| | - Meryam Sugulle
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff)
| | - Patji Alnaes-Katjavivi
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff)
| | - Heidi E S Fjeldstad
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff)
| | - Thor Ueland
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway (Drs Ueland and Lekva); K.G. Jebsen Thrombosis Research and Expertise Center, University of Tromsø, Tromsø, Norway (Dr Ueland)
| | - Tove Lekva
- Research Institute of Internal Medicine, Oslo University Hospital, Oslo, Norway (Drs Ueland and Lekva)
| | - Anne C Staff
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, Ueland, and Staff); Division of Obstetrics and Gynaecology, Oslo University Hospital, Oslo, Norway (Drs Fosheim, Jacobsen, Sugulle, Alnaes-Katjavivi, Fjeldstad, and Staff)
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23
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Siman-Tov R, Shalabi R, Shlomai A, Goldberg E, Essa W, Shusterman E, Ablin JN, Caspi M, Rosin-Arbesfeld R, Sklan EH. Elevated Serum Amyloid A Levels Contribute to Increased Platelet Adhesion in COVID-19 Patients. Int J Mol Sci 2022; 23:ijms232214243. [PMID: 36430724 PMCID: PMC9692251 DOI: 10.3390/ijms232214243] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 11/10/2022] [Accepted: 11/15/2022] [Indexed: 11/19/2022] Open
Abstract
Coronavirus disease-19 (COVID-19) patients are prone to thrombotic complications that may increase morbidity and mortality. These complications are thought to be driven by endothelial activation and tissue damage promoted by the systemic hyperinflammation associated with COVID-19. However, the exact mechanisms contributing to these complications are still unknown. To identify additional mechanisms contributing to the aberrant clotting observed in COVID-19 patients, we analyzed platelets from COVID-19 patients compared to those from controls using mass spectrometry. We identified increased serum amyloid A (SAA) levels, an acute-phase protein, on COVID-19 patients' platelets. In addition, using an in vitro adhesion assay, we showed that healthy platelets adhered more strongly to wells coated with COVID-19 patient serum than to wells coated with control serum. Furthermore, inhibitors of integrin aIIbβ3 receptors, a mediator of platelet-SAA binding, reduced platelet adhesion to recombinant SAA and to wells coated with COVID-19 patient serum. Our results suggest that SAA may contribute to the increased platelet adhesion observed in serum from COVID-19 patients. Thus, reducing SAA levels by decreasing inflammation or inhibiting SAA platelet-binding activity might be a valid approach to abrogate COVID-19-associated thrombotic complications.
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Affiliation(s)
- Ronen Siman-Tov
- Department of Clinical Microbiology and Immunology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Rulla Shalabi
- Department of Medicine F, Rabin Medical Center, Beilinson Hospital, Petah Tikva 4941492, Israel
| | - Amir Shlomai
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Department of Medicine D, Rabin Medical Center, Beilinson Hospital, Petah Tikva 4941492, Israel
| | - Elad Goldberg
- Department of Medicine F, Rabin Medical Center, Beilinson Hospital, Petah Tikva 4941492, Israel
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Wesam Essa
- Department of Medicine F, Rabin Medical Center, Beilinson Hospital, Petah Tikva 4941492, Israel
| | - Eden Shusterman
- Department of Internal Medicine H, Tel Aviv Medical Center, Tel Aviv 6423906, Israel
| | - Jacob N. Ablin
- The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Department of Internal Medicine H, Tel Aviv Medical Center, Tel Aviv 6423906, Israel
| | - Michal Caspi
- Department of Clinical Microbiology and Immunology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Rina Rosin-Arbesfeld
- Department of Clinical Microbiology and Immunology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
| | - Ella H. Sklan
- Department of Clinical Microbiology and Immunology, The Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel
- Correspondence: ; Tel.: +972-3-6408197
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Hassan SU, Chua EG, Kaur P, Paz EA, Tay CY, Greeff JC, Liu S, Martin GB. Contribution of the Immune Response in the Ileum to the Development of Diarrhoea caused by Helminth Infection: Studies with the Sheep Model. Funct Integr Genomics 2022; 22:865-877. [PMID: 35576023 PMCID: PMC9550700 DOI: 10.1007/s10142-022-00864-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 04/18/2022] [Accepted: 04/20/2022] [Indexed: 11/04/2022]
Abstract
Gastrointestinal helminths are a global health issue, for humans as well as domestic animals. Most studies focus on the tissues that are infected with the parasite, but here we studied the ileum, a tissue that is rarely infected by helminths. We tested whether inflammation in the ileum contributes to the development and severity of diarrhoea, by comparing sheep that are susceptible (n = 4) or resistant (n = 4) to the disease. We analyzed the ileum transcriptome using RNASeq sequencing approach and various bioinformatics tools including FastQC, STAR, featureCounts, DESeq2, DAVID, clusterProfiler, Cytoscape (ClusterONE) and EnrichR. We identified 243 differentially expressed genes (DEGs), of which 118 were up-regulated and 125 were down-regulated DEGs in the diarrhoea-susceptible animals compared to the diarrhoea-resistant animals. The resulting DEGs were functionally enriched for biological processes, pathways and gene set enrichment analysis. The up-regulated DEGs suggested that an inflammatory immune response was coupled with genes involved in 'Th2 immune response' and 'anti-inflammatory response'. The down-regulated DEGs were related to ion transport, muscle contraction and pathways preventing inflammation. We conclude that i) susceptibility to helminth-induced diarrhoea involves an inflammatory response at a non-infectious site; ii) down-regulation of pathways preventing inflammation can contribute to the severity of diarrhoea; and iii) genes involved in anti-inflammatory responses can reduce the inflammation and diarrhoea.
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Affiliation(s)
- Shamshad Ul Hassan
- UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA, 6009, Australia
- Helicobacter Research Laboratory, The Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Eng Guan Chua
- Helicobacter Research Laboratory, The Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Parwinder Kaur
- UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Erwin A Paz
- UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA, 6009, Australia
- Helicobacter Research Laboratory, The Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Chin Yen Tay
- Helicobacter Research Laboratory, The Marshall Centre for Infectious Disease Research and Training, School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Johan C Greeff
- UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA, 6009, Australia
- Department of Primary Industries and Regional Development, Western Australia, 3 Baron Hay Court, South Perth, WA, 6151, Australia
| | - Shimin Liu
- UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA, 6009, Australia
| | - Graeme B Martin
- UWA School of Agriculture and Environment, The University of Western Australia, Crawley, WA, 6009, Australia.
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Yao J, Wu D, Qiu Y. Adipose tissue macrophage in obesity-associated metabolic diseases. Front Immunol 2022; 13:977485. [PMID: 36119080 PMCID: PMC9478335 DOI: 10.3389/fimmu.2022.977485] [Citation(s) in RCA: 48] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2022] [Accepted: 08/18/2022] [Indexed: 11/13/2022] Open
Abstract
Adipose tissue macrophage (ATM) has been appreciated for its critical contribution to obesity-associated metabolic diseases in recent years. Here, we discuss the regulation of ATM on both metabolic homeostatsis and dysfunction. In particular, the macrophage polarization and recruitment as well as the crosstalk between ATM and adipocyte in thermogenesis, obesity, insulin resistance and adipose tissue fibrosis have been reviewed. A better understanding of how ATM regulates adipose tissue remodeling may provide novel therapeutic strategies against obesity and associated metabolic diseases.
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Affiliation(s)
- Jingfei Yao
- Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing, China
| | - Dongmei Wu
- Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
| | - Yifu Qiu
- Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing, China
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, China
- *Correspondence: Yifu Qiu,
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Lin YK, Zhu P, Wang WS, Sun K. Serum amyloid A, a host-derived DAMP in pregnancy? Front Immunol 2022; 13:978929. [PMID: 35990700 PMCID: PMC9390978 DOI: 10.3389/fimmu.2022.978929] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2022] [Accepted: 07/18/2022] [Indexed: 11/13/2022] Open
Abstract
Serum amyloid A (SAA) is one of the acute phase proteins released primarily from the liver in response to infection, inflammation and trauma. Emerging evidence indicates that SAA may function as a host-derived damage-associated molecular pattern (DAMP) protein to sense danger signals in pregnancy. The plasma SAA levels in maternal circulation are significantly increased in normal parturition, particularly in postpartum, as well as in gestational disorders such as premature preterm rupture of membranes, pre-eclampsia, gestational diabetes, and recurrent spontaneous abortion. It is likely that SAA acts as a non-specific DAMP molecule in response to inflammation and trauma experienced under these conditions. Notably, SAA can also be synthesized locally in virtually all gestational tissues. Within these gestational tissues, under the induction by bacterial products, pro-inflammatory cytokines and stress hormone glucocorticoids, SAA may exert tissue-specific effects as a toll-like receptor 4 (TLR4)-sensed DAMP molecule. SAA may promote parturition through stimulation of inflammatory reactions via induction of pro-inflammatory cytokines, chemokines, adhesion molecules and prostaglandins in the uterus, fetal membranes and placenta. In the fetal membranes, SAA may also facilitate membrane rupture through induction of matrix metalloproteases (MMPs)- and autophagy-mediated collagen breakdown and attenuation of lysyl oxidase-mediated collagen cross-linking. SAA synthesized in extravillous trophoblasts may promote their invasiveness into the endometrium in placentation. Here, we summarized the current understanding of SAA in pregnancy with an aim to stimulate in-depth investigation of SAA in pregnancy, which may help better understand how inflammation is initiated in gestational tissues in both normal and abnormal pregnancies.
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Affiliation(s)
- Yi-kai Lin
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Ping Zhu
- Department of Obstetrics and Gynecology, No.971 Hospital of the PLA Navy, Qingdao, China
| | - Wang-sheng Wang
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
| | - Kang Sun
- Center for Reproductive Medicine, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
- Shanghai Key Laboratory for Assisted Reproduction and Reproductive Genetics, Shanghai, China
- *Correspondence: Kang Sun,
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Ose J, Gigic B, Hardikar S, Lin T, Himbert C, Warby CA, Peoples AR, Lindley CL, Boehm J, Schrotz-King P, Figueiredo JC, Toriola AT, Siegel EM, Li CI, Ulrich A, Schneider M, Shibata D, Ulrich CM. Presurgery Adhesion Molecules and Angiogenesis Biomarkers Are Differently Associated with Outcomes in Colon and Rectal Cancer: Results from the ColoCare Study. Cancer Epidemiol Biomarkers Prev 2022; 31:1650-1660. [PMID: 35667092 PMCID: PMC9509698 DOI: 10.1158/1055-9965.epi-22-0092] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 05/02/2022] [Accepted: 06/03/2022] [Indexed: 02/04/2023] Open
Abstract
BACKGROUND Cell-to-cell adhesion and angiogenesis are hallmarks of cancer. No studies have examined associations of adhesion molecules and angiogenesis biomarkers with clinical outcomes in colorectal cancer. METHODS In presurgery serum from n = 426 patients with colorectal cancer (stage I-III), we investigated associations of CRP, SAA, adhesion molecules (sICAM-1, sVCAM-1), and angiogenesis markers (VEGF-A and VEGF-D) with overall survival (OS), disease-free survival (DFS), and risk of recurrence. We computed HRs and 95% confidence intervals; adjusted for age, sex, BMI, stage, site, and study site, stratified by tumor site in exploratory analyses. RESULTS N = 65 (15%) were deceased, and 39 patients (14%) had a recurrence after a median follow-up of 31 months. We observed significant associations of biomarkers with OS, DFS, and risk of recurrence on a continuous scale and comparing top to bottom tertile, with HRs ranging between 1.19 and 13.92. CRP was associated with risk of death and recurrence in patients in the top tertile compared with patients in the bottom tertile, for example, risk of recurrence HRQ3-Q1: 13.92 (1.72-112.56). Significant heterogeneity between biomarkers and clinical outcomes was observed in stratified analysis by tumor site for CRP, SAA, sICAM-1, sVCAM-1, and VEGF-D. VEGF-D was associated with a 3-fold increase in risk of death for rectal cancer (HRlog2: 3.26; 95% CI, 1.58-6.70) compared with no association for colon cancer (HRlog2: 0.78; 95% CI, 0.35-1.73; Pheterogenity = 0.01). CONCLUSIONS Adhesion molecules and angiogenesis biomarkers are independent prognostic markers for colorectal cancer, with differences by tumor site. IMPACT There is need for tailored treatment for colon and rectal cancer.
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Affiliation(s)
- Jennifer Ose
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, Salt Lake City, UT
| | | | - Sheetal Hardikar
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, Salt Lake City, UT
| | - Tengda Lin
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, Salt Lake City, UT
| | - Caroline Himbert
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, Salt Lake City, UT
| | | | - Anita R Peoples
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, Salt Lake City, UT
| | | | | | - Petra Schrotz-King
- Division of Preventive Oncology, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | | | | | - Erin M Siegel
- H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
| | | | | | | | - David Shibata
- University of Tennessee Health Science Center, Memphis, TN
| | - Cornelia M Ulrich
- University of Utah, Salt Lake City, UT
- Huntsman Cancer Institute, Salt Lake City, UT
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Tan Y, Flynn WF, Sivajothi S, Luo D, Bozal SB, Davé M, Luciano AA, Robson P, Luciano DE, Courtois ET. Single-cell analysis of endometriosis reveals a coordinated transcriptional programme driving immunotolerance and angiogenesis across eutopic and ectopic tissues. Nat Cell Biol 2022; 24:1306-1318. [PMID: 35864314 PMCID: PMC9901845 DOI: 10.1038/s41556-022-00961-5] [Citation(s) in RCA: 79] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 06/09/2022] [Indexed: 02/08/2023]
Abstract
Endometriosis is characterized by the growth of endometrial-like tissue outside the uterus. It affects many women during their reproductive age, causing years of pelvic pain and potential infertility. Its pathophysiology remains largely unknown, which limits early diagnosis and treatment. We characterized peritoneal and ovarian lesions at single-cell transcriptome resolution and compared them to matched eutopic endometrium, unaffected endometrium and organoids derived from these tissues, generating data on over 122,000 cells across 14 individuals. We spatially localized many of the cell types using imaging mass cytometry. We identify a perivascular mural cell specific to the peritoneal lesions, with dual roles in angiogenesis promotion and immune cell trafficking. We define an immunotolerant peritoneal niche, fundamental differences in eutopic endometrium and between lesion microenvironments and an unreported progenitor-like epithelial cell subpopulation. Altogether, this study provides a holistic view of the endometriosis microenvironment that represents a comprehensive cell atlas of the disease in individuals undergoing hormonal treatment, providing essential information for future therapeutics and diagnostics.
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Affiliation(s)
- Yuliana Tan
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
| | - William F Flynn
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | | | - Diane Luo
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Suleyman B Bozal
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
| | - Monica Davé
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Anthony A Luciano
- Department of Obstetrics and Gynecology, University of Connecticut School of Medicine, Farmington, CT, USA
| | - Paul Robson
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
- Department of Genetics and Genome Sciences, University of Connecticut School of Medicine, Farmington, CT, USA.
- Institute for Systems Genomics, University of Connecticut, Farmington, CT, USA.
| | - Danielle E Luciano
- Department of Obstetrics and Gynecology, University of Connecticut School of Medicine, Farmington, CT, USA.
| | - Elise T Courtois
- The Jackson Laboratory for Genomic Medicine, Farmington, CT, USA.
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Biomarkers of sepsis in pigs, horses and cattle: from acute phase proteins to procalcitonin. Anim Health Res Rev 2022; 23:82-99. [PMID: 35795920 DOI: 10.1017/s1466252322000019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Sepsis is a complex clinical syndrome triggered by an inflammatory host response to an infection. It is usually complicated to detect and diagnose, and has severe consequences in human and veterinary health, especially when treatment is not started early. Therefore, efforts to detect sepsis accurately are needed. In addition, its proper diagnosis could reduce the misuse of antibiotics, which is essential fighting against antimicrobial resistance. This case is a particular issue in farm animals, as antibiotics have been traditionally given massively, but now they are becoming increasingly restricted. When sepsis is suspected in animals, the most frequently used biomarkers are acute phase proteins such as C-reactive protein, serum amyloid A and haptoglobin, but their concentrations can increase in other inflammatory conditions. In human patients, the most promising biomarkers to detect sepsis are currently procalcitonin and presepsin, and there is a wide range of other biomarkers under study. However, there is little information on the application of these biomarkers in veterinary species. This review aims to describe the general concepts of sepsis and the current knowledge about the biomarkers of sepsis in pigs, horses, and cattle and to discuss possible advances in the field.
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Serum Amyloid A is not obligatory for high-fat, high-sucrose, cholesterol-fed diet-induced obesity and its metabolic and inflammatory complications. PLoS One 2022; 17:e0266688. [PMID: 35436297 PMCID: PMC9015120 DOI: 10.1371/journal.pone.0266688] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 03/24/2022] [Indexed: 12/26/2022] Open
Abstract
Several studies in the past have reported positive correlations between circulating Serum amyloid A (SAA) levels and obesity. However, based on limited number of studies involving appropriate mouse models, the role of SAA in the development of obesity and obesity-related metabolic consequences has not been established. Accordingly, herein, we have examined the role of SAA in the development of obesity and its associated metabolic complications in vivo using mice deficient for all three inducible forms of SAA: SAA1.1, SAA2.1 and SAA3 (TKO). Male and female mice were rendered obese by feeding a high fat, high sucrose diet with added cholesterol (HFHSC) and control mice were fed rodent chow diet. Here, we show that the deletion of SAA does not affect diet-induced obesity, hepatic lipid metabolism or adipose tissue inflammation. However, there was a modest effect on glucose metabolism. The results of this study confirm previous findings that SAA levels are elevated in adipose tissues as well as in the circulation in diet-induced obese mice. However, the three acute phase SAAs do not play a causative role in the development of obesity or obesity-associated adipose tissue inflammation and dyslipidemia.
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31
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Acute Inflammation Is a Predisposing Factor for Weight Gain and Insulin Resistance. Pharmaceutics 2022; 14:pharmaceutics14030623. [PMID: 35335996 PMCID: PMC8954490 DOI: 10.3390/pharmaceutics14030623] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2022] [Revised: 03/04/2022] [Accepted: 03/08/2022] [Indexed: 01/08/2023] Open
Abstract
In the course of infection and intense endotoxemia processes, induction of a catabolic state leading to weight loss is observed in mice and humans. However, the late effects of acute inflammation on energy homeostasis, regulation of body weight and glucose metabolism are yet to be elucidated. Here, we addressed whether serial intense endotoxemia, characterized by an acute phase response and weight loss, could be an aggravating or predisposing factor to weight gain and associated metabolic complications. Male Swiss Webster mice were submitted to 8 consecutive doses of lipopolysaccharide (10 mg/kg LPS), followed by 10 weeks on a high-fat diet (HFD). LPS-treated mice did not show changes in weight when fed standard chow. However, when challenged by a high-fat diet, LPS-treated mice showed greater weight gain, with larger fat depot areas, increased serum leptin and insulin levels and impaired insulin sensitivity when compared to mice on HFD only. Acute endotoxemia caused a long-lasting increase in mRNA expression of inflammatory markers such as TLR-4, CD14 and serum amyloid A (SAA) in the adipose tissue, which may represent the key factors connecting inflammation to increased susceptibility to weight gain and impaired glucose homeostasis. In an independent experimental model, and using publicly available microarray data from adipose tissue from mice infected with Gram-negative bacteria, we performed gene set enrichment analysis and confirmed upregulation of a set of genes responsible for cell proliferation and inflammation, including TLR-4 and SAA. Together, we showed that conditions leading to intense and recurring endotoxemia, such as common childhood bacterial infections, may resound for a long time and aggravate the effects of a western diet. If confirmed in humans, infections should be considered an additional factor contributing to obesity and type 2 diabetes epidemics.
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32
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Wang J, Yang Y, Zhang A, Zeng L, Xiao S, Ma H, Li J, Mao F, Zhang Y, Zhang Y, Yu Z, Zhang J, Xiang Z. Serum amyloid protein (SAA) as a healthy marker for immune function in Tridacna crocea. FISH & SHELLFISH IMMUNOLOGY 2022; 122:495-500. [PMID: 35202805 DOI: 10.1016/j.fsi.2022.02.038] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/13/2022] [Accepted: 02/18/2022] [Indexed: 06/14/2023]
Abstract
Serum amyloid protein (SAA) is known as an acute reactive protein of innate immunity in mammals. However, in invertebrates, the role of SAA in innate immunity is still unclear. In this study, a full-length cDNA of the SAA gene (named TcSAA) was cloned from Tridacna crocea, mollusca. The gene includes a 193 bp 5' untranslated region (UTR) and a 129 bp 3' UTR sequence, and the open reading frame (ORF) with 393 bp nucleotides encodes a polypeptide of 130 amino acids. TcSAA contains a typical signal peptide and an SAA functional domain. The mRNA expression of TcSAA was detected in all 12 selected tissues and 7 different developmental stages. Furthermore, the expression of TcSAA was increased quickly in hemocytes after challenge with V. coralliilyticus or LPS. Furthermore, rTcSAA could bind V. coralliilyticus and V. alginolyticus, and the protein could reduce the lethality rate of the clams from 80% to 55% which caused by V. coralliilyticus about 48 h after injection. In summary, these results indicate that TcSAA may act as a marker for monitoring health and protecting T. crocea.
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Affiliation(s)
- Jie Wang
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Yucheng Yang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Aijiao Zhang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Liang Zeng
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Shu Xiao
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Haitao Ma
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Jun Li
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Fan Mao
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Yuehuan Zhang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Yang Zhang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Ziniu Yu
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China
| | - Jian Zhang
- State Key Laboratory of Developmental Biology of Freshwater Fish, College of Life Sciences, Hunan Normal University, Changsha, 410081, China
| | - Zhiming Xiang
- Key Laboratory of Tropical Marine Bio-resources and Ecology, Guangdong Provincial Key Laboratory of Applied Marine Biology, South China Sea Institute of Oceanology, Chinese Academy of Science, Guangzhou, 510301, China; Innovation Academy of South China Sea Ecology and Environmental Engineering (ISEE), Chinese Academy of Sciences, Guangzhou, 510301, China.
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Robust Quantification of Regional Patterns of Migration in Three-Dimensional Cell Culture Models. J Med Biol Eng 2022. [DOI: 10.1007/s40846-022-00680-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
Abstract
Purpose
Wound healing assays is a common two-dimensional migration model, with the spheroid assay three-dimensional migration model recently emerging as being more representative of in vivo migration behaviours. These models provide insight into the overall migration of cells in response to various factors such as biological, chemotactic and molecular agents. However, currently available analysis techniques for these assays fall short on providing quantifiable means to measure regional migration patterns, which is essential to allow a more robust assessment of drug treatments on cell migration in a chemotactic fashion. Therefore, this study aims to develop a finite element (FE) based pipeline that can objectively quantify regional migration patterns of cells.
Methods
We have developed a novel FE based approach that is able to accurately measure changes in overall migration areas of 3D Glioblastoma Multiforme (GBM) spheroids that we generated using the primary cell lines from patients undergoing tumour resection surgery. We live-imaged the migration patterns of GBM spheroids and analysed them, first with the standard ImageJ method. We then performed the same analysis with the proposed FE method.
Results
When compared to the standard ImageJ method, our proposed method was able to measure the changes in a more quantitative and accurate manner. Furthermore, our regional migration analysis provided means to analyse the migration pattern seen in the phantom data and our experimental results.
Conclusion
Our FE based method will be a a robust tool for analysing cell migration patterns of GBM and other migrating cells in various diseases and degenerations.
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Shridas P, Patrick AC, Tannock LR. Role of Serum Amyloid A in Abdominal Aortic Aneurysm and Related Cardiovascular Diseases. Biomolecules 2021; 11:biom11121883. [PMID: 34944527 PMCID: PMC8699432 DOI: 10.3390/biom11121883] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 12/07/2021] [Accepted: 12/13/2021] [Indexed: 01/02/2023] Open
Abstract
Epidemiological data positively correlate plasma serum amyloid A (SAA) levels with cardiovascular disease severity and mortality. Studies by several investigators have indicated a causal role for SAA in the development of atherosclerosis in animal models. Suppression of SAA attenuates the development of angiotensin II (AngII)-induced abdominal aortic aneurysm (AAA) formation in mice. Thus, SAA is not just a marker for cardiovascular disease (CVD) development, but it is a key player. However, to consider SAA as a therapeutic target for these diseases, the pathway leading to its involvement needs to be understood. This review provides a brief description of the pathobiological significance of this enigmatic molecule. The purpose of this review is to summarize the data relevant to its role in the development of CVD, the pitfalls in SAA research, and unanswered questions in the field.
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Affiliation(s)
- Preetha Shridas
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY 40536, USA
| | - Avery C Patrick
- Pharmacology and Nutritional Sciences, University of Kentucky, Lexington, KY 40536, USA
| | - Lisa R Tannock
- Department of Internal Medicine, University of Kentucky, Lexington, KY 40536, USA
- Saha Cardiovascular Research Center, University of Kentucky, Lexington, KY 40536, USA
- Barnstable Brown Diabetes Center, University of Kentucky, Lexington, KY 40536, USA
- Veterans Affairs Lexington, University of Kentucky, Lexington, KY 40536, USA
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Patterns of serum immune biomarkers during elephant endotheliotropic herpesvirus viremia in Asian and African elephants. PLoS One 2021; 16:e0252175. [PMID: 34793450 PMCID: PMC8601435 DOI: 10.1371/journal.pone.0252175] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 11/02/2021] [Indexed: 12/23/2022] Open
Abstract
Hemorrhagic disease (HD) caused by a group of elephant endotheliotropic herpesviruses (EEHV) is one of the leading causes of death for young elephants in human care. These viruses are widespread and typically persist latently in adult elephants with no negative effects; however, in juvenile Asian and more recently young African elephants, the onset of disease can be rapid and the mortality rate high. Measuring biomarkers associated with the immune response could be beneficial to understanding underlying disease processes, as well as the management of infection and HD. The goal of this study was to measure acute phase proteins and cytokines in serum collected from elephants infected with EEHV (13 Asian and 1 African) and compare concentrations according to presence, severity and outcome of disease. Serum amyloid A (SAA) and haptoglobin (HP) were higher in elephants with EEHV viremia than those without; concentrations increased with increasing viral load, and were higher in fatal cases compared to those that survived. In Asian elephants, SAA was also higher during EEHV1 viremia compared to EEHV5. Cytokine concentrations were typically low, and no statistical differences existed between groups. However, in individuals with detectable levels, longitudinal profiles indicated changes in tumor necrosis factor alpha (TNF-α) and interleukin-2 (IL-2) that may reflect an immune response to EEHV infection. However, the overall low concentrations detected using previously validated assays do not support the presence of a 'cytokine storm' and suggest more work is needed to understand if sub-optimal immune responses could be involved in disease progression. These results highlight the potential benefit of measuring circulating biomarker concentrations, such as APPs and cytokines, to improve our understanding of EEHV viremia and HD, assist with monitoring the progression of disease and determining the impact of interventions.
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Danielsen PH, Bendtsen KM, Knudsen KB, Poulsen SS, Stoeger T, Vogel U. Nanomaterial- and shape-dependency of TLR2 and TLR4 mediated signaling following pulmonary exposure to carbonaceous nanomaterials in mice. Part Fibre Toxicol 2021; 18:40. [PMID: 34717665 PMCID: PMC8557558 DOI: 10.1186/s12989-021-00432-z] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 10/12/2021] [Indexed: 12/18/2022] Open
Abstract
Background Pulmonary exposure to high doses of engineered carbonaceous nanomaterials (NMs) is known to trigger inflammation in the lungs paralleled by an acute phase response. Toll-like receptors (TLRs), particularly TLR2 and TLR4, have recently been discussed as potential NM-sensors, initiating inflammation. Using Tlr2 and Tlr4 knock out (KO) mice, we addressed this hypothesis and compared the pattern of inflammation in lung and acute phase response in lung and liver 24 h after intratracheal instillation of three differently shaped carbonaceous NMs, spherical carbon black (CB), multi-walled carbon nanotubes (CNT), graphene oxide (GO) plates and bacterial lipopolysaccharide (LPS) as positive control.
Results The LPS control confirmed a distinct TLR4-dependency as well as a pronounced contribution of TLR2 by reducing the levels of pulmonary inflammation to 30 and 60% of levels in wild type (WT) mice. At the doses chosen, all NM caused comparable neutrophil influxes into the lungs of WT mice, and reduced levels were only detected for GO-exposed Tlr2 KO mice (35%) and for CNT-exposed Tlr4 KO mice (65%). LPS-induced gene expression was strongly TLR4-dependent. CB-induced gene expression was unaffected by TLR status. Both GO and MWCNT-induced Saa1 expression was TLR4-dependent. GO-induced expression of Cxcl2, Cxcl5, Saa1 and Saa3 were TLR2-dependent. NM-mediated hepatic acute phase response in terms of liver gene expression of Saa1 and Lcn2 was shown to depend on TLR2 for all three NMs. TLR4, in contrast, was only relevant for the acute phase response caused by CNTs, and as expected by LPS. Conclusion TLR2 and TLR4 signaling was not involved in the acute inflammatory response caused by CB exposure, but contributed considerably to that of GO and CNTs, respectively. The strong involvement of TLR2 in the hepatic acute phase response caused by pulmonary exposure to all three NMs deserves further investigations. Supplementary Information The online version contains supplementary material available at 10.1186/s12989-021-00432-z.
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Affiliation(s)
| | | | | | - Sarah Søs Poulsen
- National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Tobias Stoeger
- Comprehensive Pneumology Center (CPC)/Institute of Lung Biology and Disease (ILBD) Helmholtz Zentrum München, Neuherberg, Germany
| | - Ulla Vogel
- National Research Centre for the Working Environment, Copenhagen, Denmark. .,DTU Food, Technical University of Denmark, Kgs. Lyngby, Denmark.
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Huuska N, Netti E, Tulamo R, Lehti S, Jahromi BR, Kovanen PT, Niemelä M. Serum Amyloid A Is Present in Human Saccular Intracranial Aneurysm Walls and Associates With Aneurysm Rupture. J Neuropathol Exp Neurol 2021; 80:966-974. [PMID: 34534311 PMCID: PMC9278718 DOI: 10.1093/jnen/nlab086] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
Saccular intracranial aneurysm (sIA) rupture leads to a disabling subarachnoid hemorrhage. Chronic inflammation and lipid accumulation in the sIA wall contribute to wall degenerative remodeling that precedes its rupture. A better understanding of the pathobiological process is essential for improved future treatment of patients carrying sIAs. Serum amyloid A (SAA) is an acute-phase protein produced in response to acute and chronic inflammation and tissue damage. Here, we studied the presence and the potential role of SAA in 36 intraoperatively resected sIAs (16 unruptured and 20 ruptured), that had previously been studied by histology and immunohistochemistry. SAA was present in all sIAs, but the extent of immunopositivity varied greatly. SAA immunopositivity correlated with wall degeneration (p = 0.028) and rupture (p = 0.004), with numbers of CD163-positive and CD68-positive macrophages and CD3-positive T lymphocytes (all p < 0.001), and with the expression of myeloperoxidase, matrix metalloproteinase-9, prostaglandin E-2 receptor, and cyclo-oxygenase 2 in the sIA wall. Moreover, SAA positivity correlated with the accumulation of apolipoproteins A-1 and B-100. In conclusion, SAA occurs in the sIA wall and, as an inflammation-related factor, may contribute to the development of a rupture-prone sIA.
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Affiliation(s)
- Nora Huuska
- From the Doctoral Programme in Biomedicine, Doctoral School in Health Sciences, University of Helsinki, Helsinki, Finland.,Neurosurgery Research Group, Biomedicum, Helsinki, Finland
| | - Eliisa Netti
- Neurosurgery Research Group, Biomedicum, Helsinki, Finland.,Department of Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Riikka Tulamo
- Neurosurgery Research Group, Biomedicum, Helsinki, Finland.,Department of Vascular Surgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | - Satu Lehti
- Gerontology Research Center, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Behnam Rezai Jahromi
- Neurosurgery Research Group, Biomedicum, Helsinki, Finland.,Department of Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
| | | | - Mika Niemelä
- Department of Neurosurgery, Helsinki University Hospital and University of Helsinki, Helsinki, Finland
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Ehlting C, Wolf SD, Bode JG. Acute-phase protein synthesis: a key feature of innate immune functions of the liver. Biol Chem 2021; 402:1129-1145. [PMID: 34323429 DOI: 10.1515/hsz-2021-0209] [Citation(s) in RCA: 32] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2021] [Accepted: 07/15/2021] [Indexed: 01/08/2023]
Abstract
The expression of acute-phase proteins (APP's) maintains homeostasis and tissue repair, but also represents a central component of the organism's defense strategy, especially in the context of innate immunity. Accordingly, an inflammatory response is accompanied by significant changes in the serum protein composition, an aspect that is also used diagnostically. As the main site of APP synthesis the liver is constantly exposed to antigens or pathogens via blood flow, but also to systemic inflammatory signals originating either from the splanchnic area or from the circulation. Under both homeostatic and acute-phase response (APR) conditions the composition of APP's is determined by the pattern of regulatory mediators derived from the systemic circulation or from local cell populations, especially liver macrophages. The key regulators mentioned here most frequently are IL-1β, IL-6 and TNF-α. In addition to a variety of molecular mediators described mainly on the basis of in vitro studies, recent data emphasize the in vivo relevance of cellular key effectors as well as molecular key mediators and protein modifications for the regulation and function of APP's. These are aspects, on which the present review is primarily focused.
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Affiliation(s)
- Christian Ehlting
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Hospital of the Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Stephanie D Wolf
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Hospital of the Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany
| | - Johannes G Bode
- Clinic for Gastroenterology, Hepatology and Infectious Diseases, Hospital of the Heinrich-Heine-University, Moorenstrasse 5, D-40225 Düsseldorf, Germany
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39
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Christophersen DV, Møller P, Thomsen MB, Lykkesfeldt J, Loft S, Wallin H, Vogel U, Jacobsen NR. Accelerated atherosclerosis caused by serum amyloid A response in lungs of ApoE -/- mice. FASEB J 2021; 35:e21307. [PMID: 33638910 DOI: 10.1096/fj.202002017r] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2020] [Revised: 11/16/2020] [Accepted: 12/10/2020] [Indexed: 12/20/2022]
Abstract
Airway exposure to eg particulate matter is associated with cardiovascular disease including atherosclerosis. Acute phase genes, especially Serum Amyloid A3 (Saa3), are highly expressed in the lung following pulmonary exposure to particles. We aimed to investigate whether the human acute phase protein SAA (a homolog to mouse SAA3) accelerated atherosclerotic plaque progression in Apolipoprotein E knockout (ApoE-/- ) mice. Mice were intratracheally (i.t.) instilled with vehicle (phosphate buffered saline) or 2 µg human SAA once a week for 10 weeks. Plaque progression was assessed in the aorta using noninvasive ultrasound imaging of the aorta arch as well as by en face analysis. Additionally, lipid peroxidation, SAA3, and cholesterol were measured in plasma, inflammation was determined in lung, and mRNA levels of the acute phase genes Saa1 and Saa3 were measured in the liver and lung, respectively. Repeated i.t. instillation with SAA caused a significant progression in the atherosclerotic plaques in the aorta (1.5-fold). Concomitantly, SAA caused a statistically significant increase in neutrophils in bronchoalveolar lavage fluid (625-fold), in pulmonary Saa3 (196-fold), in systemic SAA3 (1.8-fold) and malondialdehyde levels (1.14-fold), indicating acute phase response (APR), inflammation and oxidative stress. Finally, pulmonary exposure to SAA significantly decreased the plasma levels of very low-density lipoproteins - low-density lipoproteins and total cholesterol, possibly due to lipids being sequestered in macrophages or foam cells in the arterial wall. Combined these results indicate the importance of the pulmonary APR and SAA3 for plaque progression.
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Affiliation(s)
- Daniel Vest Christophersen
- Department of Public Health, Section of Environmental Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen K, Denmark.,Ambu A/S, Ballerup, Denmark.,The National Research Centre for the Working Environment, Copenhagen, Denmark
| | - Peter Møller
- Department of Public Health, Section of Environmental Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen K, Denmark
| | - Morten Baekgaard Thomsen
- Department of Biomedical Sciences, Heart and Circulatory Research Section, Faculty of Health Sciences, University of Copenhagen, Copenhagen N, Denmark
| | - Jens Lykkesfeldt
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg C, Denmark
| | - Steffen Loft
- Department of Public Health, Section of Environmental Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen K, Denmark
| | - Håkan Wallin
- Department of Public Health, Section of Environmental Health, Faculty of Health Sciences, University of Copenhagen, Copenhagen K, Denmark.,The National Research Centre for the Working Environment, Copenhagen, Denmark.,National Institute of Occupational Health, Oslo, Norway
| | - Ulla Vogel
- The National Research Centre for the Working Environment, Copenhagen, Denmark.,Department of Micro- and Nanotechnology, Technical University of Denmark, Kgs. Lyngby, Denmark
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Davis TA, Conradie D, Shridas P, de Beer FC, Engelbrecht AM, de Villiers WJS. Serum Amyloid A Promotes Inflammation-Associated Damage and Tumorigenesis in a Mouse Model of Colitis-Associated Cancer. Cell Mol Gastroenterol Hepatol 2021; 12:1329-1341. [PMID: 34217896 PMCID: PMC8463861 DOI: 10.1016/j.jcmgh.2021.06.016] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 06/20/2021] [Accepted: 06/21/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND & AIMS Identifying new approaches to lessen inflammation, as well as the associated malignant consequences, remains crucial to improving the lives and prognosis of patients diagnosed with inflammatory bowel diseases. Although it previously has been suggested as a suitable biomarker for monitoring disease activity in patients diagnosed with Crohn's disease, the role of the acute-phase protein serum amyloid A (SAA) in inflammatory bowel disease remains unclear. In this study, we aimed to assess the role of SAA in colitis-associated cancer. METHODS We established a model of colitis-associated cancer in wild-type and SAA double-knockout (Saa1/2-/-) mice by following the azoxymethane/dextran sulfate sodium protocol. Disease activity was monitored throughout the study while colon and tumor tissues were harvested for subsequent use in cytokine analyses, Western blot, and immunohistochemistry +experiments. RESULTS We observed attenuated disease activity in mice deficient for Saa1/2 as evidenced by decreased weight loss, increased stool consistency, decreased rectal bleeding, and decreased colitis-associated tissue damage. Macrophage infiltration, including CD206+ M2-like macrophages, also was attenuated in SAA knockout mice, while levels of interleukin 4, interleukin 10, and tumor necrosis factor-ɑ were decreased in the distal colon. Mice deficient for SAA also showed a decreased tumor burden, and tumors were found to have increased apoptotic activity coupled with decreased expression for markers of proliferation. CONCLUSION Based on these findings, we conclude that SAA has an active role in inflammatory bowel disease and that it could serve as a therapeutic target aimed at decreasing chronic inflammation and the associated risk of developing colitis-associated cancer.
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Affiliation(s)
| | | | - Preetha Shridas
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Frederick C de Beer
- Department of Internal Medicine, University of Kentucky, Lexington, Kentucky
| | - Anna-Mart Engelbrecht
- Department of Physiological Sciences; African Cancer Institute, Department of Global Health
| | - Willem J S de Villiers
- African Cancer Institute, Department of Global Health; Department of Internal Medicine, Stellenbosch University, Stellenbosch, South Africa.
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Serum Amyloid A Proteins and Their Impact on Metastasis and Immune Biology in Cancer. Cancers (Basel) 2021; 13:cancers13133179. [PMID: 34202272 PMCID: PMC8267706 DOI: 10.3390/cancers13133179] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2021] [Revised: 06/19/2021] [Accepted: 06/22/2021] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The liver responds to systemic inflammation and injury in a coordinated manner, called the acute phase response. While this normal physiological response aims to restore homeostasis, malignant transformation coopts this biology to increase the risk for metastasis, immune evasion, and therapeutic resistance. In this Review, we discuss the importance of acute phase response proteins in regulating cancer biology and treatment efficacy. We also consider potential strategies to intervene on acute phase biology as an approach to improve outcomes in cancer. Abstract Cancer triggers the systemic release of inflammatory molecules that support cancer cell metastasis and immune evasion. Notably, this biology shows striking similarity to an acute phase response that is coordinated by the liver. Consistent with this, a role for the liver in defining cancer biology is becoming increasingly appreciated. Understanding the mechanisms that link acute phase biology to metastasis and immune evasion in cancer may reveal vulnerable pathways and novel therapeutic targets. Herein, we discuss a link between acute phase biology and cancer with a focus on serum amyloid A proteins and their involvement in regulating the metastatic cascade and cancer immunobiology.
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Abouelasrar Salama S, Gouwy M, Van Damme J, Struyf S. The turning away of serum amyloid A biological activities and receptor usage. Immunology 2021; 163:115-127. [PMID: 33315264 PMCID: PMC8114209 DOI: 10.1111/imm.13295] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 11/24/2020] [Accepted: 12/04/2020] [Indexed: 12/21/2022] Open
Abstract
Serum amyloid A (SAA) is an acute-phase protein (APP) to which multiple immunological functions have been attributed. Regardless, the true biological role of SAA remains poorly understood. SAA is remarkably conserved in mammalian evolution, thereby suggesting an important biological function. Since its discovery in the 1970s, the majority of researchers have investigated SAA using recombinant forms made available through bacterial expression. Nevertheless, recent studies indicate that these recombinant forms of SAA are unreliable. Indeed, commercial SAA variants have been shown to be contaminated with bacterial products including lipopolysaccharides and lipoproteins. As such, biological activities and receptor usage (TLR2, TLR4) revealed through the use of commercial SAA variants may not reflect the inherent nature of this APP. Within this review, we discuss the biological effects of SAA that have been demonstrated through more solid experimental approaches. SAA takes part in the innate immune response via the recruitment of leucocytes and executes, through pathogen recognition, antimicrobial activity. Knockout animal models implicate SAA in a range of functions, such as regulation of T-cell-mediated responses and monopoiesis. Moreover, through its structural motifs, not only does SAA function as an extracellular matrix protein, but it also binds extracellular matrix proteins. Finally, we here also provide an overview of definite SAA receptor-mediated functions and highlight those that are yet to be validated. The role of FPR2 in SAA-mediated leucocyte recruitment has been confirmed; nevertheless, SAA has been linked to a range of other receptors including CD36, SR-BI/II, RAGE and P2RX7.
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Affiliation(s)
- Sara Abouelasrar Salama
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Mieke Gouwy
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Jo Van Damme
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
| | - Sofie Struyf
- Laboratory of Molecular Immunology, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium
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43
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Chait A, Wang S, Goodspeed L, Gomes D, Turk KE, Wietecha T, Tang J, Storey C, O'Brien KD, Rubinow KB, Tang C, Vaisar T, Gharib SA, Lusis AJ, Den Hartigh LJ. Sexually Dimorphic Relationships Among Saa3 (Serum Amyloid A3), Inflammation, and Cholesterol Metabolism Modulate Atherosclerosis in Mice. Arterioscler Thromb Vasc Biol 2021; 41:e299-e313. [PMID: 33761762 PMCID: PMC8159856 DOI: 10.1161/atvbaha.121.316066] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
[Figure: see text].
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Affiliation(s)
- Alan Chait
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Shari Wang
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Leela Goodspeed
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Diego Gomes
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Katherine E Turk
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Tomasz Wietecha
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Department of Medicine, Division of Cardiology (T.W., K.D.O.), University of Washington, Seattle
| | - Jingjing Tang
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Carl Storey
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Kevin D O'Brien
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Department of Medicine, Division of Cardiology (T.W., K.D.O.), University of Washington, Seattle
| | - Katya B Rubinow
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Chongren Tang
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Tomas Vaisar
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
| | - Sina A Gharib
- Division of Pulmonary, Critical Care and Sleep Medicine, Computational Medicine Core, Department of Medicine, Center for Lung Biology (S.A.G.), University of Washington, Seattle
| | - Aldons J Lusis
- Department of Human Genetics, University of California, Los Angeles (A.J.L.)
| | - Laura J Den Hartigh
- Department of Medicine, Division of Metabolism, Endocrinology, and Nutrition (A.C., S.W., L.G., D.G., K.E.T., J.T., C.S., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
- Diabetes Institute (A.C., S.W., L.G., D.G., K.E.T., T.W., J.T., C.S., K.D.O., K.B.R., C.T., T.V., L.J.D.H.), University of Washington, Seattle
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Fourie C, Shridas P, Davis T, de Villiers WJ, Engelbrecht AM. Serum amyloid A and inflammasome activation: A link to breast cancer progression? Cytokine Growth Factor Rev 2021; 59:62-70. [DOI: 10.1016/j.cytogfr.2020.10.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 10/16/2020] [Accepted: 10/20/2020] [Indexed: 12/13/2022]
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Sabet N, Soltani Z, Khaksari M. Multipotential and systemic effects of traumatic brain injury. J Neuroimmunol 2021; 357:577619. [PMID: 34058510 DOI: 10.1016/j.jneuroim.2021.577619] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2021] [Revised: 05/07/2021] [Accepted: 05/24/2021] [Indexed: 02/06/2023]
Abstract
Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.
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Affiliation(s)
- Nazanin Sabet
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Zahra Soltani
- Endocrinology and Metabolism Research Center, Institute of Basic and Clinical Physiology Sciences, Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran; Department of Physiology and Pharmacology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran.
| | - Mohammad Khaksari
- Physiology Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
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Boakari YL, Esteller-Vico A, Loux S, El-Sheikh Ali H, Fernandes CB, Dini P, Scoggin KE, Cray C, Ball BA. Serum amyloid A, Serum Amyloid A1 and Haptoglobin in pregnant mares and their fetuses after experimental induction of placentitis. Anim Reprod Sci 2021; 229:106766. [PMID: 34015726 DOI: 10.1016/j.anireprosci.2021.106766] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2021] [Revised: 05/05/2021] [Accepted: 05/06/2021] [Indexed: 01/23/2023]
Abstract
Serum amyloid A (SAA) and Haptoglobin (Hp) are acute phase proteins, produced during inflammation, such as placentitis. In horses, SAA and SAA1 are protein coding genes. Objectives were to analyze SAA and Hp concentrations and relative abundance of SAA, SAA1 and Hp mRNA transcript in maternal and fetal tissues after experimental induction of placentitis or mares of a control group. Serum Amyloid A family proteins were in marked abundance in the stroma of the endometrium and chorioallantois associated with inflammatory cells. Maternal plasma SAA concentrations were greater (P = 0.01) in mares with experimentally induced placentitis compared to those of the control group. Maternal Hp from the groups were not different, but fetal Hp concentrations of mares with experimentally induced placentitis were greater (P = 0.02). Maternal plasma SAA and Hp concentrations were greater than fetal plasma concentrations in mares with experimentally induced placentitis (P < 0.05). Relative abundance of SAA mRNA transcript was greater in the maternal, fetal liver and chorioallantois of mares with experimentally induced placentitis (P < 0.05) compared to those in the control group. Interestingly, relative abundance of SAA1 mRNA transcript was greater in the chorioallantois of mares with experimentally induced placentitis (P < 0.05). The SAA and Hp concentrations, therefore, were greater in mares with induced placentitis. Furthermore, relative abundance of SAA1 mRNA transcript is specifically greater in the chorioallantois of mares with placentitis, which warrants further studies to elucidate the immunological response of SAA1 in the chorioallantois of mares with placentitis.
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Affiliation(s)
- Y Linhares Boakari
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA; Department of Clinical Sciences, Auburn University, Auburn, Alabama, USA
| | - A Esteller-Vico
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA; Department of Biomedical and Diagnostic Sciences, College of Veterinary Medicine, University of Tennessee, USA
| | - S Loux
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA
| | - H El-Sheikh Ali
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA; Theriogenology Department, Faculty of Veterinary Medicine, University of Mansoura, Egypt
| | - C Barbosa Fernandes
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA; Department of Animal Reproduction, School of Veterinary Medicine and Animal Science, University of São Paulo, Brazil
| | - P Dini
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA; Faculty of Veterinary Medicine, Ghent University, Merelbeke, Belgium
| | - K E Scoggin
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA
| | - C Cray
- Division of Comparative Pathology, University of Miami Miller School of Medicine, Miami, USA
| | - B A Ball
- Maxwell H. Gluck Equine Research Center, Department of Veterinary Science, University of Kentucky, Kentucky, USA.
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47
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Getachew A, Abbas N, You K, Yang Z, Hussain M, Huang X, Cheng Z, Tan S, Tao J, Yu X, Chen Y, Yang F, Pan T, Xu Y, Xu G, Zhuang Y, Wu F, Li Y. SAA1/TLR2 axis directs chemotactic migration of hepatic stellate cells responding to injury. iScience 2021; 24:102483. [PMID: 34113824 PMCID: PMC8169952 DOI: 10.1016/j.isci.2021.102483] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 04/03/2021] [Accepted: 04/25/2021] [Indexed: 12/14/2022] Open
Abstract
Hepatic stellate cells (HSCs) are crucial for liver injury repair and cirrhosis. However, the mechanism of chemotactic recruitment of HSCs into injury loci is still largely unknown. Here, we demonstrate that serum amyloid A1 (SAA1) acts as a chemokine recruiting HSCs toward injury loci signaling via TLR2, a finding proven by gene manipulation studies in cell and mice models. The mechanistic investigations revealed that SAA1/TLR2 axis stimulates the Rac GTPases through PI3K-dependent pathways and induces phosphorylation of MLC (pSer19). Genetic deletion of TLR2 and pharmacological inhibition of PI3K diminished the phosphorylation of MLCpSer19 and migration of HSCs. In brief, SAA1 serves as a hepatic endogenous chemokine for the TLR2 receptor on HSCs, thereby initiating PI3K-dependent signaling and its effector, Rac GTPases, which consequently regulates actin filament remodeling and cell directional migration. Our findings provide novel targets for anti-fibrosis drug development.
SAA1 serves as a chemokine to guide migration of HSCs toward injury locus TLR2 acts as a functional receptor for SAA1 in HSCs SAA1/TLR2 axis-mediated migration of HSCs operates through PI3K/Rac1 signaling SAA1/TLR2 axis provides a link for the cross talk between hepatocytes and HSCs
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Affiliation(s)
- Anteneh Getachew
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Nasir Abbas
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Kai You
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Zhen Yang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Muzammal Hussain
- University of China Academy of Sciences, Beijing 100049, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xinping Huang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Ziqi Cheng
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Shenglin Tan
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Jiawang Tao
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Xiaorui Yu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yan Chen
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Fan Yang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Tingcai Pan
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yingying Xu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Guosheng Xu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yuanqi Zhuang
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - FeiMa Wu
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China
| | - Yinxiong Li
- Institute of Public Health, Guangzhou Institute of Biomedicine and Health, Chinese Academy of Sciences, 190 Kaiyuan Avenue, Science Park, Guangzhou, Guangdong 510530, China.,University of China Academy of Sciences, Beijing 100049, China.,Key Laboratory of Regenerative Biology, South China Institute for Stem Cell Biology and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangdong Provincial Key Laboratory of Biocomputing, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China.,Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China
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48
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Cohen G. Effect of High-Density Lipoprotein from Healthy Subjects and Chronic Kidney Disease Patients on the CD14 Expression on Polymorphonuclear Leukocytes. Int J Mol Sci 2021; 22:ijms22062830. [PMID: 33799511 PMCID: PMC7998954 DOI: 10.3390/ijms22062830] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 02/26/2021] [Accepted: 03/08/2021] [Indexed: 01/22/2023] Open
Abstract
In uremic patients, high-density lipoprotein (HDL) loses its anti-inflammatory features and can even become pro-inflammatory due to an altered protein composition. In chronic kidney disease (CKD), impaired functions of polymorphonuclear leukocytes (PMNLs) contribute to inflammation and an increased risk of cardiovascular disease. This study investigated the effect of HDL from CKD and hemodialysis (HD) patients on the CD14 expression on PMNLs. HDL was isolated using a one-step density gradient centrifugation. Isolation of PMNLs was carried out by discontinuous Ficoll-Hypaque density gradient centrifugation. CD14 surface expression was quantified by flow cytometry. The activity of the small GTPase Rac1 was determined by means of an activation pull-down assay. HDL increased the CD14 surface expression on PMNLs. This effect was more pronounced for HDL isolated from uremic patients. The acute phase protein serum amyloid A (SAA) caused higher CD14 expression, while SAA as part of an HDL particle did not. Lipid raft disruption with methyl-β-cyclodextrin led to a reduced CD14 expression in the absence and presence of HDL. HDL from healthy subjects but not from HD patients decreased the activity of Rac1. Considering the known anti-inflammatory effects of HDL, the finding that even HDL from healthy subjects increased the CD14 expression was unexpected. The pathophysiological relevance of this result needs further investigation.
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Affiliation(s)
- Gerald Cohen
- Department of Nephrology and Dialysis, Medical University of Vienna, A-1090 Vienna, Austria
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49
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Gaun A, Lewis Hardell KN, Olsson N, O'Brien JJ, Gollapudi S, Smith M, McAlister G, Huguet R, Keyser R, Buffenstein R, McAllister FE. Automated 16-Plex Plasma Proteomics with Real-Time Search and Ion Mobility Mass Spectrometry Enables Large-Scale Profiling in Naked Mole-Rats and Mice. J Proteome Res 2021; 20:1280-1295. [PMID: 33499602 DOI: 10.1021/acs.jproteome.0c00681] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
Performing large-scale plasma proteome profiling is challenging due to limitations imposed by lengthy preparation and instrument time. We present a fully automated multiplexed proteome profiling platform (AutoMP3) using the Hamilton Vantage liquid handling robot capable of preparing hundreds to thousands of samples. To maximize protein depth in single-shot runs, we combined 16-plex Tandem Mass Tags (TMTpro) with high-field asymmetric waveform ion mobility spectrometry (FAIMS Pro) and real-time search (RTS). We quantified over 40 proteins/min/sample, doubling the previously published rates. We applied AutoMP3 to investigate the naked mole-rat plasma proteome both as a function of the circadian cycle and in response to ultraviolet (UV) treatment. In keeping with the lack of synchronized circadian rhythms in naked mole-rats, we find few circadian patterns in plasma proteins over the course of 48 h. Furthermore, we quantify many disparate changes between mice and naked mole-rats at both 48 h and one week after UV exposure. These species differences in plasma protein temporal responses could contribute to the pronounced cancer resistance observed in naked mole-rats. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE [1] partner repository with the dataset identifier PXD022891.
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Affiliation(s)
- Aleksandr Gaun
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Kaitlyn N Lewis Hardell
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States.,Cancer Prevention Fellowship Program, Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland 20892-7315, United States
| | - Niclas Olsson
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Jonathon J O'Brien
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Sudha Gollapudi
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Megan Smith
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Graeme McAlister
- Thermo Fisher Scientific, San Jose, California 95134, United States
| | - Romain Huguet
- Thermo Fisher Scientific, San Jose, California 95134, United States
| | - Robert Keyser
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Rochelle Buffenstein
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
| | - Fiona E McAllister
- Calico Life Sciences LLC, South San Francisco, California 94080-7095, United States
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50
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Badawi R, Asghar MN, Abd-Elsalam S, Elshweikh SA, Haydara T, Alnabawy SM, Elkadeem M, ElKhalawany W, Soliman S, Elkhouly R, Soliman S, Watany M, Khalif M, Elfert A. Amyloid A in Serum and Ascitic Fluid as a Novel Diagnostic Marker of Spontaneous Bacterial Peritonitis. Antiinflamm Antiallergy Agents Med Chem 2021; 19:140-148. [PMID: 30931865 PMCID: PMC7475799 DOI: 10.2174/1871523018666190401154447] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2019] [Revised: 03/13/2019] [Accepted: 03/21/2019] [Indexed: 12/18/2022]
Abstract
Background: Diagnosis of Spontaneous Bacterial Peritonitis (SBP) depends mainly on ascetic fluid culture which may be negative in spite of the clinical suggestion of SBP and high ascetic fluid neutrophilic count. Aims: This study aimed to evaluate the biological importance of amyloid A biomarker in both serum and ascetic fluid to diagnose SBP as early as possible and to compare it to other markers (C-reactive protein (CRP), and the neutrophil-to-lymphocyte ratio (NLR)). Methods: This study included 37 patients with hepatic ascites; twenty-two of them had SBP, and 15 patients did not have SBP. Serum and ascetic fluid amyloid A, ascetic fluid neutrophil, C-reactive protein, and neutrophil-to-lymphocyte ratio were measured in all subjects before the start of antimicrobial chemotherapy to the infected ones. Results: Both the serum and ascetic fluid amyloid and also, CRP were significantly higher in patients infected with ascetic fluid than others. The cut-off point of serum amyloid A for early detection of SBP was 9.25ug/ml with the high sensitivity and specificity. For ascetic amyloid A, the sensitivity and specificity were 90.09% and 60% at cut-off point 2.85ug/ml, respectively. Conclusion: Amyloid A in serum and ascitic fluid can be considered as a good biomarker for early diagnosis of SBP.
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Affiliation(s)
- Rehab Badawi
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Muhammad N Asghar
- Department of Biosciences, Abo Akademi University, 20500 Turku, Finland.,Department of Medical Biology, University of Quebec at Trois-Riveres, Quebec, Canada
| | - Sherief Abd-Elsalam
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | | | - Tamer Haydara
- Internal Medicine Department, Kafr-Elsheikh University, Kafr El- Shaikh, Egypt
| | | | - Mahmoud Elkadeem
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Walaa ElKhalawany
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Samah Soliman
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Reham Elkhouly
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Shimaa Soliman
- Public Health and Community Medicine, Faculty of Medicine, Menoufia University Menoufia, Egypt
| | - Mona Watany
- Clinical Pathology, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Mai Khalif
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
| | - Asem Elfert
- Tropical Medicine and Infectious Diseases, Faculty of Medicine, Tanta University, Tanta, Egypt
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