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1
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Srivastava S, Rasool M. Genetics, epigenetics and autoimmunity constitute a Bermuda triangle for the pathogenesis of rheumatoid arthritis. Life Sci 2024; 357:123075. [PMID: 39341491 DOI: 10.1016/j.lfs.2024.123075] [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: 07/23/2024] [Revised: 09/13/2024] [Accepted: 09/22/2024] [Indexed: 10/01/2024]
Abstract
Rheumatoid arthritis (RA), a multigene disorder with a heritability rate of 60 %, is characterized by persistent pain, synovial hyperplasia, and cartilage and bone destruction, ultimately causing irreversible joint deformity. The etiology and pathogenesis of rheumatoid arthritis (RA) are primarily influenced by specific genetic variants, particularly HLA alleles such as HLA-DRB1*01 and DRB1*04. However, other HLA alleles such as HLA-DRB1*10 and DPB*1 have also been found to contribute to increased susceptibility to RA. However, non-HLA genes also confer a comparatively high risk of RA disease manifestation. The most relevant single nucleotide polymorphisms (SNPs) associated with non-HLA genes are PTPN22, TRAF1, CXCL-12, TBX-5, STAT4, FCGR, PADI4, and MTHFR. In conjunction with genetic susceptibility, epigenetic alterations orchestrate paramount involvement in regulating RA pathogenesis. Increasing evidence implicates DNA methylation and histone protein modifications, including acetylation and methylation, as the primary epigenetic mechanisms that drive the pathogenesis and clinical progression of the disease. In addition to genetic and epigenetic changes, autoimmune inflammation also determines the pathological progression of the synovial membrane in joints with RA. Glycosylation changes, such as sialylation and fucosylation, in immune cells have been shown to be relevant to disease progression. Genetic heterogeneity, epigenetic factors, and changes in glycosylation do not fully explain the features of RA. Therefore, investigating the interplay between genetics, epigenetics, and autoimmunity is crucial. This review highlights the significance and interaction of these elements in RA pathophysiology, suggesting their diagnostic potential and opening new avenues for novel therapeutic approaches.
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Affiliation(s)
- Susmita Srivastava
- Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India
| | - Mahaboobkhan Rasool
- Immunopathology Lab, School of Biosciences and Technology, Vellore Institute of Technology (VIT), Vellore 632 014, Tamil Nadu, India.
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2
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Nardini E, Rodriguez E, van Kooyk Y. The tissue glycome as regulator of immune activation and tolerance mediated by C-type lectins and Siglecs. Semin Immunol 2024; 76:101913. [PMID: 39602867 DOI: 10.1016/j.smim.2024.101913] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Revised: 11/20/2024] [Accepted: 11/20/2024] [Indexed: 11/29/2024]
Abstract
The immune system is a complex network of highly specialized microenvironments, denominated niches, which arise from dynamic interactions between immune and parenchymal cells as well as acellular components such as structural elements and local molecular signals. A critical, yet underexplored, layer shaping these niches is the glycome, the complete repertoire of glycans and glycoconjugates produced by cells. The glycome is prevalent in the outer membrane of cells and their secreted components, and can be sensed by glycan binding receptors on immune cells. These receptors detect changes in glycosylation and consequently modulate immune cell activity, trafficking, and signalling, altering homeostasis. Tissues like the brain and the placenta are prone to accommodate tolerance, while the gut and the thymus are sensitive to inflammation. We provide here an overview of current literature that shows the impact of altered glycosylation of tissues on host immune cells and how interference in this process may lead to new diagnostics and immune therapeutics, aiming to restore the immune balance in autoimmunity and cancer.
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Affiliation(s)
- Eleonora Nardini
- Amsterdam UMC location Vrije Universiteit Amsterdam, Molecular Cell Biology and Immunology, De Boelelaan, Amsterdam 1117, The Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands; Amsterdam institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands
| | - Ernesto Rodriguez
- Amsterdam UMC location Vrije Universiteit Amsterdam, Molecular Cell Biology and Immunology, De Boelelaan, Amsterdam 1117, The Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands; Amsterdam institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands
| | - Yvette van Kooyk
- Amsterdam UMC location Vrije Universiteit Amsterdam, Molecular Cell Biology and Immunology, De Boelelaan, Amsterdam 1117, The Netherlands; Cancer Center Amsterdam, Cancer Biology and Immunology, Amsterdam, The Netherlands; Amsterdam institute for Infection and Immunity, Cancer Immunology, Amsterdam, The Netherlands.
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3
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Skurska E, Olczak M. Interplay between de novo and salvage pathways of GDP-fucose synthesis. PLoS One 2024; 19:e0309450. [PMID: 39446915 PMCID: PMC11501016 DOI: 10.1371/journal.pone.0309450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2024] [Accepted: 08/12/2024] [Indexed: 10/26/2024] Open
Abstract
GDP-fucose is synthesised via two pathways: de novo and salvage. The first uses GDP-mannose as a substrate, and the second uses free fucose. To date, these pathways have been considered to work separately and not to have an influence on each other. We report the mutual response of the de novo and salvage pathways to the lack of enzymes from a particular route of GDP-fucose synthesis. We detected different efficiencies of GDP-fucose and fucosylated structure synthesis after a single inactivation of enzymes of the de novo pathway. Our study demonstrated the unequal influence of the salvage enzymes on the production of GDP-fucose by enzymes of the de novo biosynthesis pathway. Simultaneously, we detected an elevated level of one of the enzymes of the de novo pathway in the cell line lacking the enzyme of the salvage biosynthesis pathway. Additionally, we identified dissimilarities in fucose uptake between cells lacking TSTA3 and GMDS proteins.
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Affiliation(s)
- Edyta Skurska
- Department of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
| | - Mariusz Olczak
- Department of Biochemistry, Faculty of Biotechnology, University of Wroclaw, Wroclaw, Poland
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4
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Wen W, Hu X, Liu J, Zeng F, Xu Y, Yuan Y, Gao C, Sun X, Cheng B, Wang J, Hu X, Xiao RP, Chen X, Zhang X. RIP3 regulates doxorubicin-induced intestinal mucositis via FUT2-mediated α-1,2-fucosylation. Inflamm Res 2024; 73:1781-1801. [PMID: 39180691 DOI: 10.1007/s00011-024-01932-2] [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: 06/03/2024] [Revised: 07/24/2024] [Accepted: 08/05/2024] [Indexed: 08/26/2024] Open
Abstract
OBJECTIVE Intestinal mucositis is one of the common side effects of anti-cancer chemotherapy. However, the molecular mechanisms involved in mucositis development remain incompletely understood. In this study, we investigated the function of receptor-interacting protein kinase 3 (RIP3/RIPK3) in regulating doxorubicin-induced intestinal mucositis and its potential mechanisms. METHODS Intestinal mucositis animal models were induced in mice for in vivo studies. Rat intestinal cell line IEC-6 was used for in vitro studies. RNA‑seq was used to explore the transcriptomic changes in doxorubicin-induced intestinal mucositis. Intact glycopeptide characterization using mass spectrometry was applied to identify α-1,2-fucosylated proteins associated with mucositis. RESULTS Doxorubicin treatment increased RIP3 expression in the intestine and caused severe intestinal mucositis in the mice, depletion of RIP3 abolished doxorubicin-induced intestinal mucositis. RIP3-mediated doxorubicin-induced mucositis did not depend on mixed lineage kinase domain-like (MLKL) but on α-1,2-fucosyltransferase 2 (FUT2)-catalyzed α-1,2-fucosylation on inflammation-related proteins. Deficiency of MLKL did not affect intestinal mucositis, whereas inhibition of α-1,2-fucosylation by 2-deoxy-D-galactose (2dGal) profoundly attenuated doxorubicin-induced inflammation and mucositis. CONCLUSIONS RIP3-FUT2 pathway is a central node in doxorubicin-induced intestinal mucositis. Targeting intestinal RIP3 and/or FUT2-mediated α-1,2-fucosylation may provide potential targets for preventing chemotherapy-induced intestinal mucositis.
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Affiliation(s)
- Wei Wen
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
- PKU-Nanjing Institute of Translational Medicine, Nanjing, 211800, China
| | - Xiaomin Hu
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Jialin Liu
- College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
- Beijing National Laboratory for Molecular Sciences, Peking University, Beijing, 100871, China
| | - Fanxin Zeng
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
- Department of Clinical Research Center, Dazhou Central Hospital, Dazhou, 635000, China
| | - Yihua Xu
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Ye Yuan
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Chunyan Gao
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Xueting Sun
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Bo Cheng
- College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China
- Beijing National Laboratory for Molecular Sciences, Peking University, Beijing, 100871, China
| | - Jue Wang
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Xinli Hu
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China
| | - Rui-Ping Xiao
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.
- PKU-Nanjing Institute of Translational Medicine, Nanjing, 211800, China.
- State Key Laboratory of Biomembrane and Membrane Biotechnology, Peking University, Beijing, 100871, China.
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
| | - Xing Chen
- College of Chemistry and Molecular Engineering, Peking University, Beijing, 100871, China.
- Beijing National Laboratory for Molecular Sciences, Peking University, Beijing, 100871, China.
- Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
- Synthetic and Functional Biomolecules Center, Peking University, Beijing, 100871, China.
- Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education, Peking University, Beijing, 100871, China.
| | - Xiuqin Zhang
- Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
- Beijing Key Laboratory of Cardiometabolic Molecular Medicine, Peking University, Beijing, 100871, China.
- PKU-Nanjing Institute of Translational Medicine, Nanjing, 211800, China.
- National Biomedical Imaging Center, School of Future Technology, Peking University, Beijing, 100871, China.
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5
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Kao MR, Ma TH, Chou HY, Chang SC, Cheng LC, Liao KS, Shie JJ, Harris PJ, Wong CH, Hsieh YSY. A Robust α-l-Fucosidase from Prevotella nigrescens for Glycoengineering Therapeutic Antibodies. ACS Chem Biol 2024; 19:1515-1524. [PMID: 38912881 PMCID: PMC11267573 DOI: 10.1021/acschembio.4c00196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2024] [Revised: 06/07/2024] [Accepted: 06/10/2024] [Indexed: 06/25/2024]
Abstract
Eliminating the core fucose from the N-glycans of the Fc antibody segment by pathway engineering or enzymatic methods has been shown to enhance the potency of therapeutic antibodies, especially in the context of antibody-dependent cytotoxicity (ADCC). However, there is a significant challenge due to the limited defucosylation efficiency of commercially available α-l-fucosidases. In this study, we report a unique α-l-fucosidase (PnfucA) from the bacterium Prevotella nigrescens that has a low sequence identity compared with all other known α-l-fucosidases and is highly reactive toward a core disaccharide substrate with fucose α(1,3)-, α (1,4)-and α(1,6)-linked to GlcNAc, and is less reactive toward the Fuc-α(1,2)-Gal on the terminal trisaccharide of the oligosaccharide Globo H (Bb3). The kinetic properties of the enzyme, such as its Km and kcat, were determined and the optimized expression of PnfucA gave a yield exceeding 30 mg/L. The recombinant enzyme retained its full activity even after being incubated for 6 h at 37 °C. Moreover, it retained 92 and 87% of its activity after freezing and freeze-drying treatments, respectively, for over 28 days. In a representative glycoengineering of adalimumab (Humira), PnfucA showed remarkable hydrolytic efficiency in cleaving the α(1,6)-linked core fucose from FucGlcNAc on the antibody with a quantitative yield. This enabled the seamless incorporation of biantennary sialylglycans by Endo-S2 D184 M in a one-pot fashion to yield adalimumab in a homogeneous afucosylated glycoform with an improved binding affinity toward Fcγ receptor IIIa.
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Affiliation(s)
- Mu-Rong Kao
- School
of Pharmacy, College of Pharmacy, Taipei
Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan
- Genomics
Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei 115201, Taiwan
- Division
of Glycoscience, Department of Chemistry, School of Engineering Sciences
in Chemistry, Biotechnology and Health, Royal Institute of Technology
(KTH), AlbaNova University Centre, Stockholm SE-10691, Sweden
| | - Tzu-Hsuan Ma
- School
of Pharmacy, College of Pharmacy, Taipei
Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan
- Division
of Glycoscience, Department of Chemistry, School of Engineering Sciences
in Chemistry, Biotechnology and Health, Royal Institute of Technology
(KTH), AlbaNova University Centre, Stockholm SE-10691, Sweden
| | - Hsiang-Yu Chou
- School
of Pharmacy, College of Pharmacy, Taipei
Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan
| | - Shu-Chieh Chang
- Division
of Glycoscience, Department of Chemistry, School of Engineering Sciences
in Chemistry, Biotechnology and Health, Royal Institute of Technology
(KTH), AlbaNova University Centre, Stockholm SE-10691, Sweden
| | - Lin-Chen Cheng
- School
of Pharmacy, College of Pharmacy, Taipei
Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan
| | - Kuo-Shiang Liao
- Genomics
Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei 115201, Taiwan
| | - Jiun-Jie Shie
- Institute
of Chemistry, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei 115201, Taiwan
| | - Philip J. Harris
- School
of Biological Sciences, The University of
Auckland, Auckland Mail Centre, Private Bag 92019, Auckland 1142, New Zealand
| | - Chi-Huey Wong
- Genomics
Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei 115201, Taiwan
- Department
of Chemistry, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, California 92037, United States
| | - Yves S. Y. Hsieh
- School
of Pharmacy, College of Pharmacy, Taipei
Medical University, No. 250 Wuxing Street, Taipei 11031, Taiwan
- Genomics
Research Center, Academia Sinica, No. 128 Academia Road, Section 2, Nankang District, Taipei 115201, Taiwan
- Division
of Glycoscience, Department of Chemistry, School of Engineering Sciences
in Chemistry, Biotechnology and Health, Royal Institute of Technology
(KTH), AlbaNova University Centre, Stockholm SE-10691, Sweden
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6
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Fazelzadeh Haghighi M, Jafari Khamirani H, Fallahi J, Monfared AA, Ashrafi Dehkordi K, Tabei SMB. Novel insight into FCSK-congenital disorder of glycosylation through a CRISPR-generated cell model. Mol Genet Genomic Med 2024; 12:e2445. [PMID: 38722107 PMCID: PMC11080630 DOI: 10.1002/mgg3.2445] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2023] [Revised: 04/08/2024] [Accepted: 04/23/2024] [Indexed: 05/12/2024] Open
Abstract
BACKGROUND FCSK-congenital disorder of glycosylation (FCSK-CDG) is a recently discovered rare autosomal recessive genetic disorder with defective fucosylation due to mutations in the fucokinase encoding gene, FCSK. Despite the essential role of fucokinase in the fucose salvage pathway and severe multisystem manifestations of FCSK-CDG patients, it is not elucidated which cells or which types of fucosylation are affected by its deficiency. METHODS In this study, CRISPR/Cas9 was employed to construct an FCSK-CDG cell model and explore the molecular mechanisms of the disease by lectin flow cytometry and real-time PCR analyses. RESULTS Comparison of cellular fucosylation by lectin flow cytometry in the created CRISPR/Cas9 FCSK knockout and the same unedited cell lines showed no significant change in the amount of cell surface fucosylated glycans, which is consistent with the only documented previous study on different cell types. It suggests a probable effect of this disease on secretory glycoproteins. Investigating O-fucosylation by analysis of the NOTCH3 gene expression as a potential target revealed a significant decrease in the FCSK knockout cells compared with the same unedited ones, proving the effect of fucokinase deficiency on EGF-like repeats O-fucosylation. CONCLUSION This study expands insight into the FCSK-CDG molecular mechanism; to the best of our knowledge, it is the first research conducted to reveal a gene whose expression level alters due to this disease.
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Affiliation(s)
- Maryam Fazelzadeh Haghighi
- Department of Molecular Medicine, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | | | - Jafar Fallahi
- Molecular Medicine Department, School of Advanced Medical Sciences and TechnologiesShiraz University of Medical SciencesShirazIran
| | - Ali Arabi Monfared
- Central Research LaboratoryShiraz University of Medical SciencesShirazIran
| | - Korosh Ashrafi Dehkordi
- Department of Molecular Medicine, School of Advanced TechnologiesShahrekord University of Medical SciencesShahrekordIran
| | - Seyed Mohammad Bagher Tabei
- Department of Medical GeneticsShiraz University of Medical SciencesShirazIran
- Maternal‐Fetal Medicine Research CenterShiraz University of Medical SciencesShirazIran
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7
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Keisham S, Saito S, Kowashi S, Tateno H. Droplet-Based Glycan and RNA Sequencing for Profiling the Distinct Cellular Glyco-States in Single Cells. SMALL METHODS 2024; 8:e2301338. [PMID: 38164999 DOI: 10.1002/smtd.202301338] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/02/2023] [Revised: 12/18/2023] [Indexed: 01/03/2024]
Abstract
Plate-based single-cell glycan and RNA sequencing (scGR-seq) is previously developed to realize the integrated analysis of glycome and transcriptome in single cells. However, the sample size is limited to only a few hundred cells. Here, a droplet-based scGR-seq is developed to address this issue by adopting a 10x Chromium platform to simultaneously profile ten thousand cells' glycome and transcriptome in single cells. To establish droplet-based scGR-seq, a comparative analysis of two distinct cell lines is performed: pancreatic ductal adenocarcinoma cells and normal pancreatic duct cells. Droplet-based scGR-seq revealed distinct glycan profiles between the two cell lines that showed a strong correlation with the results obtained by flow cytometry. Next, droplet-based scGR-seq is applied to a more complex sample: peripheral blood mononuclear cells (PBMC) containing various immune cells. The method can systematically map the glycan signature for each immune cell in PBMC as well as glycan alterations by cell lineage. Prediction of the association between the glycan expression and the gene expression using regression analysis ultimately leads to the identification of a glycan epitope that impacts cellular functions. In conclusion, the droplet-based scGR-seq realizes the high-throughput profiling of the distinct cellular glyco-states in single cells.
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Affiliation(s)
- Sunanda Keisham
- Cellular and Molecular Biotechnology Research Institute, Multicellular System Regulation Research Group, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan
- Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, 305-8566, Japan
| | - Sayoko Saito
- Cellular and Molecular Biotechnology Research Institute, Multicellular System Regulation Research Group, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan
| | - Satori Kowashi
- Cellular and Molecular Biotechnology Research Institute, Multicellular System Regulation Research Group, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan
| | - Hiroaki Tateno
- Cellular and Molecular Biotechnology Research Institute, Multicellular System Regulation Research Group, National Institute of Advanced Industrial Science and Technology (AIST), Central 6, 1-1-1 Higashi, Tsukuba, Ibaraki, 305-8566, Japan
- Ph.D. Program in Human Biology, School of Integrative and Global Majors, University of Tsukuba, Tsukuba, Ibaraki, 305-8566, Japan
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8
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Muchowicz A, Bartoszewicz A, Zaslona Z. The Exploitation of the Glycosylation Pattern in Asthma: How We Alter Ancestral Pathways to Develop New Treatments. Biomolecules 2024; 14:513. [PMID: 38785919 PMCID: PMC11117584 DOI: 10.3390/biom14050513] [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: 03/21/2024] [Revised: 04/12/2024] [Accepted: 04/21/2024] [Indexed: 05/25/2024] Open
Abstract
Asthma has reached epidemic levels, yet progress in developing specific therapies is slow. One of the main reasons for this is the fact that asthma is an umbrella term for various distinct subsets. Due to its high heterogeneity, it is difficult to establish biomarkers for each subset of asthma and to propose endotype-specific treatments. This review focuses on protein glycosylation as a process activated in asthma and ways to utilize it to develop novel biomarkers and treatments. We discuss known and relevant glycoproteins whose functions control disease development. The key role of glycoproteins in processes integral to asthma, such as inflammation, tissue remodeling, and repair, justifies our interest and research in the field of glycobiology. Altering the glycosylation states of proteins contributing to asthma can change the pathological processes that we previously failed to inhibit. Special emphasis is placed on chitotriosidase 1 (CHIT1), an enzyme capable of modifying LacNAc- and LacdiNAc-containing glycans. The expression and activity of CHIT1 are induced in human diseased lungs, and its pathological role has been demonstrated by both genetic and pharmacological approaches. We propose that studying the glycosylation pattern and enzymes involved in glycosylation in asthma can help in patient stratification and in developing personalized treatment.
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Affiliation(s)
| | | | - Zbigniew Zaslona
- Molecure S.A., Zwirki i Wigury 101, 02-089 Warszawa, Poland; (A.M.); (A.B.)
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9
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Burton C, Bitaraf A, Snyder K, Zhang C, Yoder SJ, Avram D, Du D, Yu X, Lau EK. The functional role of L-fucose on dendritic cell function and polarization. Front Immunol 2024; 15:1353570. [PMID: 38646527 PMCID: PMC11026564 DOI: 10.3389/fimmu.2024.1353570] [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: 12/10/2023] [Accepted: 02/21/2024] [Indexed: 04/23/2024] Open
Abstract
Despite significant advances in the development and refinement of immunotherapies administered to combat cancer over the past decades, a number of barriers continue to limit their efficacy. One significant clinical barrier is the inability to mount initial immune responses towards the tumor. As dendritic cells are central initiators of immune responses in the body, the elucidation of mechanisms that can be therapeutically leveraged to enhance their functions to drive anti-tumor immune responses is urgently needed. Here, we report that the dietary sugar L-fucose can be used to enhance the immunostimulatory activity of dendritic cells (DCs). L-fucose polarizes immature myeloid cells towards specific DC subsets, specifically cDC1 and moDC subsets. In vitro, L-fucose treatment enhances antigen uptake and processing of DCs. Furthermore, our data suggests that L-fucose-treated DCs increase stimulation of T cell populations. Consistent with our functional assays, single-cell RNA sequencing of intratumoral DCs from melanoma- and breast tumor-bearing mice confirmed transcriptional regulation and antigen processing as pathways that are significantly altered by dietary L-fucose. Together, this study provides the first evidence of the ability of L-fucose to bolster DC functionality and provides rational to further investigate how L-fucose can be used to leverage DC function in order to enhance current immunotherapy.
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Affiliation(s)
- Chase Burton
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, United States
- Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Amirreza Bitaraf
- Cancer Biology Ph.D. Program, University of South Florida, Tampa, FL, United States
- Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Kara Snyder
- Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Molecular Medicine, University of South Florida, Tampa, FL, United States
| | - Chaomei Zhang
- Molecular Genomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Sean J. Yoder
- Molecular Genomics Core, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Dorina Avram
- Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Dongliang Du
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Xiaoqing Yu
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
| | - Eric K. Lau
- Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
- Department of Tumor Microenvironment and Metastasis, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, United States
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10
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Drzewicka K, Zasłona Z. Metabolism-driven glycosylation represents therapeutic opportunities in interstitial lung diseases. Front Immunol 2024; 15:1328781. [PMID: 38550597 PMCID: PMC10973144 DOI: 10.3389/fimmu.2024.1328781] [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: 10/27/2023] [Accepted: 02/23/2024] [Indexed: 04/02/2024] Open
Abstract
Metabolic changes are coupled with alteration in protein glycosylation. In this review, we will focus on macrophages that are pivotal in the pathogenesis of pulmonary fibrosis and sarcoidosis and thanks to their adaptable metabolism are an attractive therapeutic target. Examples presented in this review demonstrate that protein glycosylation regulates metabolism-driven immune responses in macrophages, with implications for fibrotic processes and granuloma formation. Targeting proteins that regulate glycosylation, such as fucosyltransferases, neuraminidase 1 and chitinase 1 could effectively block immunometabolic changes driving inflammation and fibrosis, providing novel avenues for therapeutic interventions.
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Sołkiewicz K, Kokot I, Dymicka-Piekarska V, Dorf J, Kratz EM. Are Changes in Serum IgG Glycosylation Related to the Severe Course of SARS-CoV-2 Infection and Recovery Process? In Search of New Diagnostic and Prognostic Biomarkers. J Inflamm Res 2024; 17:1413-1427. [PMID: 38450051 PMCID: PMC10916521 DOI: 10.2147/jir.s439005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2023] [Accepted: 02/16/2024] [Indexed: 03/08/2024] Open
Abstract
Introduction Immunoglobulin G (IgG) glycosylation affects its effector functions and is essential in many steps of the inflammatory cascade. Therefore, it may be an important parameter for assessing the body's immune response during the course of COVID-19 (Coronavirus disease 2019). Methods The N- and O-glycosylation of serum IgG in severe COVID-19 patients (n=87), convalescents (n=50), and healthy subjects (n=65) were examined using a modified lectin-ELISA method with specific biotinylated lectins. The obtained data were analyzed using STATISTICA 13.3PL software. Results We showed significantly higher expression of Lewisx oligosaccharide structures in severe COVID-19 patients than in the other two groups. Moreover, significantly lower expression of Lewisy sugar structures in IgG glycans was observed in the convalescents when compared with COVID-19 patients and healthy subjects. The lowest expression of highly branched N-glycans in cases of severe COVID-19 indicates that the development of the disease is associated with the presence of typical IgG biantennary N-glycans. The lack of significant differences in the expression of Tn antigen in IgG between studied groups and the significantly lower expression of T antigen in convalescents compared to the patients with severe COVID-19 and healthy subjects indicates a decrease in the content of the T antigen in IgG O-glycans in subjects recovered from COVID-19. Substantially higher reactivities of IgG O-glycans with Jacalin observed in COVID-19 patients and convalescents in comparison to the control group were most probably caused by increased expression of core 3 O-glycans in IgG. Conclusion Severe COVID-19 is accompanied by the expression in serum IgG of sialylated biantennary and highly branched N-glycans, decorated by fucose of Lewisx and Lewisy structures. The higher reactivity of IgG O-glycans with Jacalin in severe COVID-19 patients and convalescents indicates that the disease development and the recovery process are most probably accompanied by increased expression of the core 3 O-glycans.
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Affiliation(s)
- Katarzyna Sołkiewicz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | - Izabela Kokot
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
| | | | - Justyna Dorf
- Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Ewa Maria Kratz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, Poland
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12
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Ko JH, Ryu JS, Oh JH, Oh JY. Splenocytes with fucosylation deficiency promote T cell proliferation and differentiation through thrombospondin-1 downregulation. Immunology 2024; 171:262-269. [PMID: 37957948 DOI: 10.1111/imm.13716] [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: 06/02/2023] [Accepted: 10/31/2023] [Indexed: 11/15/2023] Open
Abstract
Fucosylation plays a critical role in cell-to-cell interactions and disease progression. However, the effects of fucosylation on splenocytes and their interactions with T cells remain unclear. In this study, we aimed to explore the transcriptome profiles of splenocytes deficient in fucosyltransferase (FUT) 1, an enzyme that mediates fucosylation, and investigate their impact on the proliferation and differentiation of T cells. We analysed and compared the transcriptomes of splenocytes isolated from Fut1 knockout (KO) mice and those from wild-type (WT) mice using RNA-seq. Additionally, we examined the effects of Fut1 KO splenocytes on CD4 T cell proliferation and differentiation, in comparison to WT splenocytes, and elucidated the mechanisms involved. The comparative analysis of transcriptomes between Fut1 KO and WT splenocytes revealed that thrombospondin-1, among the genes related to immune response and inflammation, was the most highly downregulated gene in Fut1 KO splenocytes. The reduced expression of thrombospondin-1 was further confirmed using qRT-PCR and flow cytometry. In coculture experiments, Fut1 KO splenocytes promoted the proliferation of CD4 T cells and drove their differentiation toward Th1 and Th17 cells, compared with WT splenocytes. Moreover, the levels of IL-2, IFN-γ and IL-17 were increased, while IL-10 was decreased, in T cells cocultured with Fut1 KO splenocytes compared with those with WT splenocytes. These effects of Fut1 KO splenocytes on T cells were reversed when thrombospondin-1 was replenished. Taken together, our results demonstrate that splenocytes with Fut1 deficiency promote CD4 T cell proliferation and Th1/Th17 differentiation at least in part through thrombospondin-1 downregulation.
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Affiliation(s)
- Jung Hwa Ko
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Jin Suk Ryu
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
| | - Jang-Hee Oh
- Department of Dermatology, Seoul National University College of Medicine, Seoul, Korea
| | - Joo Youn Oh
- Laboratory of Ocular Regenerative Medicine and Immunology, Biomedical Research Institute, Seoul National University Hospital, Seoul, Korea
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, Korea
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13
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Zhong J, Li J, Burton GJ, Koistinen H, Cheung KW, Ng EHY, Yao Y, Yeung WSB, Lee CL, Chiu PCN. The functional roles of protein glycosylation in human maternal-fetal crosstalk. Hum Reprod Update 2024; 30:81-108. [PMID: 37699855 DOI: 10.1093/humupd/dmad024] [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: 04/28/2023] [Revised: 07/20/2023] [Indexed: 09/14/2023] Open
Abstract
BACKGROUND The establishment of maternal-fetal crosstalk is vital to a successful pregnancy. Glycosylation is a post-translational modification in which glycans (monosaccharide chains) are attached to an organic molecule. Glycans are involved in many physiological and pathological processes. Human endometrial epithelium, endometrial gland secretions, decidual immune cells, and trophoblasts are highly enriched with glycoconjugates and glycan-binding molecules important for a healthy pregnancy. Aberrant glycosylation in the placenta and uterus has been linked to repeated implantation failure and various pregnancy complications, but there is no recent review summarizing the functional roles of glycosylation at the maternal-fetal interface and their associations with pathological processes. OBJECTIVE AND RATIONALE This review aims to summarize recent findings on glycosylation, glycosyltransferases, and glycan-binding receptors at the maternal-fetal interface, and their involvement in regulating the biology and pathological conditions associated with endometrial receptivity, placentation and maternal-fetal immunotolerance. Current knowledge limitations and future insights into the study of glycobiology in reproduction are discussed. SEARCH METHODS A comprehensive PubMed search was conducted using the following keywords: glycosylation, glycosyltransferases, glycan-binding proteins, endometrium, trophoblasts, maternal-fetal immunotolerance, siglec, selectin, galectin, repeated implantation failure, early pregnancy loss, recurrent pregnancy loss, preeclampsia, and fetal growth restriction. Relevant reports published between 1980 and 2023 and studies related to these reports were retrieved and reviewed. Only publications written in English were included. OUTCOMES The application of ultrasensitive mass spectrometry tools and lectin-based glycan profiling has enabled characterization of glycans present at the maternal-fetal interface and in maternal serum. The endometrial luminal epithelium is covered with highly glycosylated mucin that regulates blastocyst adhesion during implantation. In the placenta, fucose and sialic acid residues are abundantly presented on the villous membrane and are essential for proper placentation and establishment of maternal-fetal immunotolerance. Glycan-binding receptors, including selectins, sialic-acid-binding immunoglobulin-like lectins (siglecs) and galectins, also modulate implantation, trophoblast functions and maternal-fetal immunotolerance. Aberrant glycosylation is associated with repeated implantation failure, early pregnancy loss and various pregnancy complications. The current limitation in the field is that most glycobiological research relies on association studies, with few studies revealing the specific functions of glycans. Technological advancements in analytic, synthetic and functional glycobiology have laid the groundwork for further exploration of glycans in reproductive biology under both physiological and pathological conditions. WIDER IMPLICATIONS A deep understanding of the functions of glycan structures would provide insights into the molecular mechanisms underlying their involvement in the physiological and pathological regulation of early pregnancy. Glycans may also potentially serve as novel early predictive markers and therapeutic targets for repeated implantation failure, pregnancy loss, and other pregnancy complications.
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Affiliation(s)
- Jiangming Zhong
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China
- The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Jianlin Li
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China
| | - Graham J Burton
- Department of Physiology, Development and Neuroscience, University of Cambridge, Cambridge, UK
| | - Hannu Koistinen
- Department of Clinical Chemistry and Haematology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ka Wang Cheung
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China
| | - Ernest H Y Ng
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China
- The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Yuanqing Yao
- The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - William S B Yeung
- The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Cheuk-Lun Lee
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China
- The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
| | - Philip C N Chiu
- Department of Obstetrics and Gynaecology, School of Clinical Medicine, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong S.A.R., China
- The University of Hong Kong Shenzhen Key Laboratory of Fertility Regulation, The University of Hong Kong-Shenzhen Hospital, Shenzhen, China
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Scheper AF, Schofield J, Bohara R, Ritter T, Pandit A. Understanding glycosylation: Regulation through the metabolic flux of precursor pathways. Biotechnol Adv 2023; 67:108184. [PMID: 37290585 DOI: 10.1016/j.biotechadv.2023.108184] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2023] [Revised: 05/29/2023] [Accepted: 05/31/2023] [Indexed: 06/10/2023]
Abstract
Glycosylation is how proteins and lipids are modified with complex carbohydrates known as glycans. The post-translational modification of proteins with glycans is not a template-driven process in the same way as genetic transcription or protein translation. Glycosylation is instead dynamically regulated by metabolic flux. This metabolic flux is determined by the concentrations and activities of the glycotransferase enzymes, which synthesise glycans, the metabolites that act as their precursors and transporter proteins. This review provides an overview of the metabolic pathways underlying glycan synthesis. Pathological dysregulation of glycosylation, particularly increased glycosylation occurring during inflammation, is also elucidated. The resulting inflammatory hyperglycosylation acts as a glycosignature of disease, and we report on the changes in the metabolic pathways which feed into glycan synthesis, revealing alterations to key enzymes. Finally, we examine studies in developing metabolic inhibitors targeting these critical enzymes. These results provide the tools for researchers investigating the role of glycan metabolism in inflammation and have helped to identify promising glycotherapeutic approaches to inflammation.
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Affiliation(s)
- Aert F Scheper
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Ireland
| | - Jack Schofield
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Ireland
| | - Raghvendra Bohara
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Ireland
| | - Thomas Ritter
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Ireland; School of Medicine, University of Galway, Ireland; Regenerative Medicine Institute (REMEDI), University of Galway, Ireland
| | - Abhay Pandit
- CÚRAM, SFI Research Centre for Medical Devices, University of Galway, Ireland.
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15
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Mao K, Luo J, Ye J, Li L, Lin F, Zhou M, Wang D, Yu L, Zhu Z, Zuo D, Ye J. 2-D-gal Targets Terminal Fucosylation to Inhibit T-cell Response in a Mouse Skin Transplant Model. Transplantation 2023; 107:1291-1301. [PMID: 36367925 DOI: 10.1097/tp.0000000000004408] [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: 11/13/2022]
Abstract
BACKGROUND Organ allograft rejection is mainly driven by T-cell response. Studies have shown that fucosylation plays essential roles in the immune cell development and function. Terminal fucosylation inhibitor, 2-deoxy-D-galactose (2-D-gal), has been reported to suppress immunoresponse of macrophages, but its effects on T-cell-mediated immune response and transplant rejection have not been fully explored. METHODS The terminal fucosylation level in T cells was detected through ulex europaeus agglutinin-I staining. The consequences of 2-D-gal on murine T-cell proliferation, activation, cytokine secretion, and cell cycle were investigated in vitro. T-cell receptor signaling cascades were examined. Last, mouse skin transplant model was utilized to evaluate the regulatory effects of 2-D-gal on T-cell response in vivo. RESULTS The expression of fucosyltransferase1 was upregulated in CD3/CD28-activated T cells along with an elevation of α(1,2)-fucosylation level as seen by ulex europaeus agglutinin-I staining. Furthermore, 2-D-gal suppressed T-cell activation and proliferation, decrease cytokines production, arrest cell cycle, and prevent the activation of T-cell receptor signaling cascades. In vivo experiments showed that 2-D-gal limited T-cell proliferation to prolong skin allograft in mice. This was accompanied by lower level of inflammatory cytokines, and were comparable to those treated with Cyclosporin A. CONCLUSIONS Terminal fucosylation appears to play a role in T-cell activation and proliferation, and its inhibitor, 2-D-gal, can suppress T-cell activation and proliferation both in vitro and in vivo. In a therapeutic context, inhibiting terminal fucosylation may be a potential strategy to prevent allogeneic transplant rejection.
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Affiliation(s)
- Kaifeng Mao
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Jialiang Luo
- Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Junli Ye
- Department of Physiology and Pathophysiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Lei Li
- Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Fenwang Lin
- Department of Kidney Transplantation, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Minjie Zhou
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Di Wang
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, China
| | - Lu Yu
- Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengyumeng Zhu
- Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Daming Zuo
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Junsheng Ye
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
- Department of Kidney Transplantation, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
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Luo J, Mao K, Zhu Z, Ye J, Li L, Wang D, Zhou J, Lin F, Li J, Ye J. FUT1-mediated terminal fucosylation acts as a new target to attenuate renal fibrosis. Mol Med 2023; 29:55. [PMID: 37085770 PMCID: PMC10122342 DOI: 10.1186/s10020-023-00639-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/19/2023] [Indexed: 04/23/2023] Open
Abstract
BACKGROUNDS Renal fibrosis is a common pathologic process of most chronic kidney diseases (CKDs), becoming one of the major public health problems worldwide. Terminal fucosylation plays an important role in physiological homeostasis and pathological development. The present study aimed to explore the role of terminal fucosylation during kidney fibrogenesis and propose a possible anti-fibrosis treatment via suppressing aberrant terminal fucosylation. METHODS We investigated the expression level of fucosyltransferase1 (FUT1) in CKD patients by using public database. Then, we further confirmed the level of terminal fucosylation by UEA-I staining and FUT1 expression in unilateral ureteral obstruction (UUO)-induced renal fibrosis mice. Immunostaining, qPCR, western blotting and wound healing assay were applied to reveal the effect of FUT1 overexpression in human kidney proximal tubular epithelial cell (HK-2). What's more, we applied terminal fucosylation inhibitor, 2-Deoxy-D-galactose (2-D-gal), to determine whether suppressing terminal fucosylation ameliorates renal fibrosis progression in vitro and in vivo. RESULTS Here, we found that the expression of FUT1 significantly increased during renal fibrosis. In vitro experiments showed upregulation of epithelial-mesenchymal transition (EMT) after over-expression of FUT1 in HK-2. Furthermore, in vivo and in vitro experiments indicated that suppression of terminal fucosylation, especially on TGF-βR I and II, could alleviate fibrogenesis via inhibiting transforming growth factor-β (TGF-β)/Smad signaling. CONCLUSIONS The development of kidney fibrosis is attributed to FUT1-mediated terminal fucosylation, shedding light on the inhibition of terminal fucosylation as a potential therapeutic treatment against renal fibrosis.
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Affiliation(s)
- Jialiang Luo
- Department of Dermatology, the Fifth Affiliated Hospital, Southern Medical University, Guangzhou, Guangdong, 510900, China.
| | - Kaifeng Mao
- Department of Kidney Transplantation, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Zhengyumeng Zhu
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Junli Ye
- Department of Physiology and Pathophysiology, School of Basic Medicine, Medical College, Qingdao University, Qingdao, China
| | - Lei Li
- Department of Medical Laboratory, School of Laboratory Medicine and Biotechnology, Southern Medical University, Guangzhou, Guangdong, China
| | - Di Wang
- Department of Dermatology, Dermatology Hospital of Southern Medical University, Southern Medical University, Guangzhou, Guangdong, China
| | - Jia Zhou
- Department of Immunology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, China
| | - Fenwang Lin
- Department of Kidney Transplantation, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China
| | - Juan Li
- School of Nursing, Southern Medical University, Guangzhou, Guangdong, 510900, China.
| | - Junsheng Ye
- Department of Kidney Transplantation, Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, 102218, China.
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Antonarelli G, Pieri V, Porta FM, Fusco N, Finocchiaro G, Curigliano G, Criscitiello C. Targeting Post-Translational Modifications to Improve Combinatorial Therapies in Breast Cancer: The Role of Fucosylation. Cells 2023; 12:cells12060840. [PMID: 36980181 PMCID: PMC10047715 DOI: 10.3390/cells12060840] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2023] [Revised: 03/03/2023] [Accepted: 03/05/2023] [Indexed: 03/30/2023] Open
Abstract
Various tumors rely on post-translational modifications (PTMs) to promote invasiveness and angiogenesis and to reprogram cellular energetics to abate anti-cancer immunity. Among PTMs, fucosylation is a particular type of glycosylation that has been linked to different aspects of immune and hormonal physiological functions as well as hijacked by many types of tumors. Multiple tumors, including breast cancer, have been linked to dismal prognoses and increased metastatic potential due to fucosylation of the glycan core, namely core-fucosylation. Pre-clinical studies have examined the molecular mechanisms regulating core-fucosylation in breast cancer models, its negative prognostic value across multiple disease stages, and the activity of in vivo pharmacological inhibition, instructing combinatorial therapies and translation into clinical practice. Throughout this review, we describe the role of fucosylation in solid tumors, with a particular focus on breast cancer, as well as physiologic conditions on the immune system and hormones, providing a view into its potential as a biomarker for predicating or predicting cancer outcomes, as well as a potential clinical actionability as a biomarker.
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Affiliation(s)
- Gabriele Antonarelli
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
| | - Valentina Pieri
- Neural Stem Cell Biology Unit, Division of Neuroscience, IRCCS San Raffaele Hospital, 20132 Milan, Italy
- Vita-Salute San Raffaele University, 20132 Milan, Italy
| | - Francesca Maria Porta
- Division of Pathology, European Institute of Oncology (IEO), IRCCS, 20141 Milan, Italy
- School of Pathology, University of Milan, 20122 Milan, Italy
| | - Nicola Fusco
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
- Division of Pathology, European Institute of Oncology (IEO), IRCCS, 20141 Milan, Italy
| | | | - Giuseppe Curigliano
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
| | - Carmen Criscitiello
- Division of New Drugs and Early Drug Development for Innovative Therapies, European Institute of Oncology, IRCCS, 20139 Milan, Italy
- Department of Oncology and Hemato-Oncology (DIPO), University of Milan, 20122 Milan, Italy
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Yang X, Ma L, Zhang J, Chen L, Zou Z, Shen D, He H, Zhang L, Chen J, Yuan Z, Qin X, Yu C. Hypofucosylation of Unc5b regulated by Fut8 enhances macrophage emigration and prevents atherosclerosis. Cell Biosci 2023; 13:13. [PMID: 36670464 PMCID: PMC9854080 DOI: 10.1186/s13578-023-00959-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2022] [Accepted: 01/08/2023] [Indexed: 01/21/2023] Open
Abstract
BACKGROUND Atherosclerosis (AS) is the leading underlying cause of the majority of clinical cardiovascular events. Retention of foamy macrophages in plaques is the main factor initiating and promoting the atherosclerotic process. Our previous work showed that ox-LDL induced macrophage retention in plaques and that the guidance receptor Uncoordinated-5 homolog B (Unc5b) was involved in this process. However, little is known about the role of Unc5b in regulating macrophage accumulation within plaques. RESULTS In the present study, we found that Unc5b controls macrophage migration and thus promotes plaque progression in ApoE-/- mice. The immunofluorescence colocalization assay results first suggested that fucosyltransferase 8 (Fut8) might participate in the exacerbation of atherosclerosis. Animals with Unc5b overexpression showed elevated levels of Fut8 and numbers of macrophages and an increased lesion size and intimal thickness. However, these effects were reversed in ApoE-/- mice with Unc5b knockdown. Furthermore, Raw264.7 macrophages with siRNA-mediated silencing of Unc5b or overexpression of Unc5b were used to confirm the regulatory mechanisms of Unc5b and Fut8 in vitro. In response to ox-LDL exposure, Unc5b and Fut8 were both upregulated, and macrophages showed reduced pseudopod formation and migratory capacities. However, these capacities were restored by blocking Unc5b or Fut8. Furthermore, the IP assay indicated that Fut8 regulated the level of α-1,6 fucosylation of Unc5b, which mainly occurs in the endoplasmic reticulum (ER), and genetic deletion of the main fucosylation sites or Fut8 resulted in hypofucosylation of Unc5b. Moreover, the macrophage migration mediated by Unc5b depended on inactivation of the p-CDC42/p-PAK pathway. Conversely, macrophages with Unc5b overexpression displayed activation of the p-CDC42/p-PAK pathway and decreased migration both in vivo and in vitro. CONCLUSION These results demonstrated that hypofucosylation of Unc5b regulated by Fut8 is positively associated with the delay of the atherosclerotic process by promoting the migration of foamy macrophages. These findings identify a promising therapeutic target for atherosclerosis.
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Affiliation(s)
- Xi Yang
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China ,grid.410612.00000 0004 0604 6392College of Basic Medicine, Inner Mongolia Medical University, Hohhot, 010110 China
| | - Limei Ma
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Jun Zhang
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Linmu Chen
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Zhen Zou
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Di Shen
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Hui He
- grid.203458.80000 0000 8653 0555Institute of Life Sciences, Chongqing Medical University, Chongqing, 400016 China
| | - Lei Zhang
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Jun Chen
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Zhiyi Yuan
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Xia Qin
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
| | - Chao Yu
- grid.203458.80000 0000 8653 0555College of Pharmacy, Chongqing Medical University, Chongqing, 400016 China
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19
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Li P, Chen Z, You S, Xu Y, Hao Z, Liu D, Shen J, Zhu B, Dan W, Sun S. Application of StrucGP in medical immunology: site-specific N-glycoproteomic analysis of macrophages. Front Med 2022; 17:304-316. [PMID: 36580234 DOI: 10.1007/s11684-022-0964-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 09/06/2022] [Indexed: 12/30/2022]
Abstract
The structure of N-glycans on specific proteins can regulate innate and adaptive immunity via sensing environmental signals. Meanwhile, the structural diversity of N-glycans poses analytical challenges that limit the exploration of specific glycosylation functions. In this work, we used THP-1-derived macrophages as examples to show the vast potential of a N-glycan structural interpretation tool StrucGP in N-glycoproteomic analysis. The intact glycopeptides of macrophages were enriched and analyzed using mass spectrometry (MS)-based glycoproteomic approaches, followed by the large-scale mapping of site-specific glycan structures via StrucGP. Results revealed that bisected GlcNAc, core fucosylated, and sialylated glycans (e.g., HexNAc4Hex5Fuc1Neu5Ac1, N4H5F1S1) were increased in M1 and M2 macrophages, especially in the latter. The findings indicated that these structures may be closely related to macrophage polarization. In addition, a high level of glycosylated PD-L1 was observed in M1 macrophages, and the LacNAc moiety was detected at Asn-192 and Asn-200 of PD-L1, and Asn-200 contained Lewis epitopes. The precision structural interpretation of site-specific glycans and subsequent intervention of target glycoproteins and related glycosyltransferases are of great value for the development of new diagnostic and therapeutic approaches for different diseases.
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Affiliation(s)
- Pengfei Li
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Zexuan Chen
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Shanshan You
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Yintai Xu
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Zhifang Hao
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Didi Liu
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Jiechen Shen
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Bojing Zhu
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Wei Dan
- College of Life Sciences, Northwest University, Xi'an, 710069, China
| | - Shisheng Sun
- College of Life Sciences, Northwest University, Xi'an, 710069, China.
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20
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Wang L, Xu H, Yang H, Zhou J, Zhao L, Zhang F. Glucose metabolism and glycosylation link the gut microbiota to autoimmune diseases. Front Immunol 2022; 13:952398. [PMID: 36203617 PMCID: PMC9530352 DOI: 10.3389/fimmu.2022.952398] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2022] [Accepted: 08/19/2022] [Indexed: 11/21/2022] Open
Abstract
Carbohydrates serve as important energy sources and structural substances for human body as well as for gut microbes. As evidenced by the advances in immunometabolism, glucose metabolism and adenosine triphosphate (ATP) generation are deeply involved in immune cell activation, proliferation, and signaling transduction as well as trafficking and effector functions, thus contributing to immune response programming and assisting in host adaption to microenvironment changes. Increased glucose uptake, aberrant expression of glucose transporter 1 (e.g., GLU1), and abnormal glycosylation patterns have been identified in autoimmunity and are suggested as partially responsible for the dysregulated immune response and the modification of gut microbiome composition in the autoimmune pathogenesis. The interaction between gut microbiota and host carbohydrate metabolism is complex and bidirectional. Their impact on host immune homeostasis and the development of autoimmune diseases remains to be elucidated. This review summarized the current knowledge on the crosstalk of glucose metabolism and glycosylation in the host with intestinal microbiota and discussed their possible role in the development and progression of autoimmune diseases. Potential therapeutic strategies targeting glucose metabolism and glycosylation in modulating gut ecosystem and treating autoimmune diseases were discussed as well.
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Affiliation(s)
- Lu Wang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, Beijing, China
| | - Haojie Xu
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, Beijing, China
| | - Huaxia Yang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
| | - Jiaxin Zhou
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Jiaxin Zhou, ; Lidan Zhao,
| | - Lidan Zhao
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
- *Correspondence: Jiaxin Zhou, ; Lidan Zhao,
| | - Fengchun Zhang
- Department of Rheumatology and Clinical Immunology, Peking Union Medical College Hospital, National Clinical Research Center for Dermatologic and Immunologic Diseases (NCRC-DID), Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
- Key Laboratory of Rheumatology and Clinical Rheumatology, Ministry of Education, Beijing, China
- State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Beijing, China
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21
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Radovani B, Gudelj I. N-Glycosylation and Inflammation; the Not-So-Sweet Relation. Front Immunol 2022; 13:893365. [PMID: 35833138 PMCID: PMC9272703 DOI: 10.3389/fimmu.2022.893365] [Citation(s) in RCA: 55] [Impact Index Per Article: 18.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 05/30/2022] [Indexed: 12/28/2022] Open
Abstract
Chronic inflammation is the main feature of many long-term inflammatory diseases such as autoimmune diseases, metabolic disorders, and cancer. There is a growing number of studies in which alterations of N-glycosylation have been observed in many pathophysiological conditions, yet studies of the underlying mechanisms that precede N-glycome changes are still sparse. Proinflammatory cytokines have been shown to alter the substrate synthesis pathways as well as the expression of glycosyltransferases required for the biosynthesis of N-glycans. The resulting N-glycosylation changes can further contribute to disease pathogenesis through modulation of various aspects of immune cell processes, including those relevant to pathogen recognition and fine-tuning the inflammatory response. This review summarizes our current knowledge of inflammation-induced N-glycosylation changes, with a particular focus on specific subsets of immune cells of innate and adaptive immunity and how these changes affect their effector functions, cell interactions, and signal transduction.
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Affiliation(s)
- Barbara Radovani
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
| | - Ivan Gudelj
- Department of Biotechnology, University of Rijeka, Rijeka, Croatia
- Genos Glycoscience Research Laboratory, Zagreb, Croatia
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22
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Yu Y, Lu Q, Chen F, Wang S, Niu C, Liao J, Wang H, Chen F. Serum untargeted metabolomics analysis of the mechanisms of evodiamine on type 2 diabetes mellitus model rats. Food Funct 2022; 13:6623-6635. [PMID: 35635367 DOI: 10.1039/d1fo04396j] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Evodiamine (EVO) is an alkaloid extracted from Evodia rutaecarpa and has various pharmacological activities, including hypolipidemic, anti-inflammatory, anti-infective, and antitumor effects. However, the therapeutic effects of EVO on type 2 diabetes mellitus (T2DM) and the possible mechanisms remain unknown. In this study, we used a T2DM rat model using a high-fat diet (HFD) combined with streptozotocin (STZ) injections followed by treatment with EVO. First, we evaluated the therapeutic effects of EVO on T2DM rats, following which we evaluated the anti-inflammatory and anti-oxidative effects of EVO on T2DM rats. Finally, we analyzed the metabolic regulatory mechanism of EVO in T2DM rats using an untargeted metabolomics approach. The results showed that EVO treatment alleviated the hyperglycemia, hyperlipidemia, insulin resistance (IR), and pathological changes of the liver, pancreas and kidneys in T2DM rats. Moreover, EVO treatment ameliorated the oxidative stress and decreased the serum levels of pro-inflammatory cytokines in T2DM model rats. Serum untargeted metabolomics analysis indicated that the EVO treatment affected the levels of 26 metabolites, such as methionine, citric acid, cholesterol, taurocholic acid, pilocarpine, adrenic acid, and other metabolites. These metabolites were mainly related to the amino sugar and nucleotide sugar metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, and tryptophan metabolism pathways. In conclusion, EVO can reduce blood glucose and improve oxidative stress and inflammatory response in T2DM rats. These functions are related to the regulation of amino sugar and nucleotide sugar metabolism, arginine biosynthesis, arginine and proline metabolism, glutathione metabolism, and tryptophan metabolism pathways.
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Affiliation(s)
- Yuejie Yu
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
| | - Qinyan Lu
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
| | - Feng Chen
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
| | - Shangli Wang
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
| | - Chunxiang Niu
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
| | - Jiabao Liao
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
| | - Hongwu Wang
- Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China.
| | - Fengjuan Chen
- Jiaxing Hospital of Traditional Chinese Medicine, Jiaxing 314001, China.
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23
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Shoda J, Tanaka S, Etori K, Hattori K, Kasuya T, Ikeda K, Maezawa Y, Suto A, Suzuki K, Nakamura J, Maezawa Y, Takemoto M, Betsholtz C, Yokote K, Ohtori S, Nakajima H. Semaphorin 3G exacerbates joint inflammation through the accumulation and proliferation of macrophages in the synovium. Arthritis Res Ther 2022; 24:134. [PMID: 35659346 PMCID: PMC9166515 DOI: 10.1186/s13075-022-02817-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2022] [Accepted: 05/17/2022] [Indexed: 02/07/2023] Open
Abstract
Objectives Methotrexate (MTX) is an anchor drug for the treatment of rheumatoid arthritis (RA). However, the precise mechanisms by which MTX stalls RA progression and alleviates the ensuing disease effects remain unknown. The aim of the present study was to identify novel therapeutic target molecules, the expression patterns of which are affected by MTX in patients with RA. Methods CD4+ T cells from 28 treatment-naïve patients with RA before and 3 months after the initiation of MTX treatment were subjected to DNA microarray analyses. The expression levels of semaphorin 3G, a differentially expressed gene, and its receptor, neuropilin-2, were evaluated in the RA synovium and collagen-induced arthritis synovium. Collagen-induced arthritis and collagen antibody-induced arthritis were induced in semaphorin3G-deficient mice and control mice, and the clinical score, histological score, and serum cytokines were assessed. The migration and proliferation of semaphorin 3G-stimulated bone marrow-derived macrophages were analyzed in vitro. The effect of local semaphorin 3G administration on the clinical score and number of infiltrating macrophages during collagen antibody-induced arthritis was evaluated. Results Semaphorin 3G expression in CD4+ T cells was downregulated by MTX treatment in RA patients. It was determined that semaphorin 3G is expressed in RA but not in the osteoarthritis synovium; its receptor neuropilin-2 is primarily expressed on activated macrophages. Semaphorin3G deficiency ameliorated collagen-induced arthritis and collagen antibody-induced arthritis. Semaphorin 3G stimulation enhanced the migration and proliferation of bone marrow-derived macrophages. Local administration of semaphorin 3G deteriorated collagen antibody-induced arthritis and increased the number of infiltrating macrophages. Conclusions Upregulation of semaphorin 3G in the RA synovium is a novel mechanism that exacerbates joint inflammation, leading to further deterioration, through macrophage accumulation.
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Affiliation(s)
- Jumpei Shoda
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.,Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Shigeru Tanaka
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Keishi Etori
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Koto Hattori
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tadamichi Kasuya
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kei Ikeda
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yuko Maezawa
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Akira Suto
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Kotaro Suzuki
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Junichi Nakamura
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Yoshiro Maezawa
- Department of Endocrinology, Hematology, and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Minoru Takemoto
- Department of Endocrinology, Hematology, and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan.,Department of Medicine, Division of Diabetes, Metabolism and Endocrinology, International University of Health and Welfare, Narita, Japan
| | - Christer Betsholtz
- Department of Immunology, Genetics and Pathology (IGP), Uppsala University, Uppsala, Sweden
| | - Koutaro Yokote
- Department of Endocrinology, Hematology, and Gerontology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Seiji Ohtori
- Department of Orthopedic Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroshi Nakajima
- Department of Allergy and Clinical Immunology, Graduate School of Medicine, Chiba University, Chiba, Japan.
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24
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Glittenberg MT, Kounatidis I, Atilano M, Ligoxygakis P. A genetic screen in Drosophila reveals the role of fucosylation in host susceptibility to Candida infection. Dis Model Mech 2022; 15:dmm049218. [PMID: 35142345 PMCID: PMC9118035 DOI: 10.1242/dmm.049218] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Accepted: 01/26/2022] [Indexed: 11/20/2022] Open
Abstract
Candida infections constitute a blind spot in global public health as very few new anti-fungal drugs are being developed. Genetic surveys of host susceptibilities to such infections using mammalian models have certain disadvantages in that obtaining results is time-consuming, owing to relatively long lifespans, and these results have low statistical resolution because sample sizes are usually small. Here, we report a targeted genetic screening of 5698 RNAi lines encompassing 4135 Drosophila genes with human homologues, several of which we identify as important for host survival after Candida albicans infection. These include genes in a variety of functional classes encompassing gene expression, intracellular signalling, metabolism and enzymatic regulation. Analysis of one of the screen hits, the infection-induced α-(1,3)-fucosylase FucTA, showed that N-glycan fucosylation has several targets among proteins involved in host defence, which provides multiple avenues of investigation for the mechanistic analysis of host survival to systemic C. albicans infection.
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Affiliation(s)
- Marcus T. Glittenberg
- Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, UK
| | - Ilias Kounatidis
- Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, UK
| | - Magda Atilano
- Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, UK
| | - Petros Ligoxygakis
- Department of Biochemistry, University of Oxford, South Parks Rd, Oxford OX1 3QU, UK
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25
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Adhikari E, Liu Q, Burton C, Mockabee-Macias A, Lester DK, Lau E. l-fucose, a sugary regulator of antitumor immunity and immunotherapies. Mol Carcinog 2022; 61:439-453. [PMID: 35107186 DOI: 10.1002/mc.23394] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 12/20/2022]
Abstract
l-fucose is a dietary sugar that is used by cells in a process called fucosylation to posttranslationally modify and regulate protein behavior and function. As fucosylation plays essential cellular functions in normal organ and immune developmental and homeostasis, it is perhaps not surprising that it has been found to be perturbed in a number of pathophysiological contexts, including cancer. Increasing studies over the years have highlighted key roles that altered fucosylation can play in cancer cell-intrinsic as well as paracrine signaling and interactions. In particular, studies have demonstrated that fucosylation impact tumor:immunological interactions and significantly enhance or attenuate antitumor immunity. Importantly, fucosylation appears to be a posttranslational modification that can be therapeutically targeted, as manipulating the molecular underpinnings of fucosylation has been shown to be sufficient to impair or block tumor progression and to modulate antitumor immunity. Moreover, the fucosylation of anticancer agents, such as therapeutic antibodies, has been shown to critically impact their efficacy. In this review, we summarize the underappreciated roles that fucosylation plays in cancer and immune cells, as well as the fucosylation of therapeutic antibodies or the manipulation of fucosylation and their implications as new therapeutic modalities for cancer.
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Affiliation(s)
- Emma Adhikari
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Qian Liu
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Chase Burton
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Department of Immunology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Immunology Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Andrea Mockabee-Macias
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Daniel K Lester
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
| | - Eric Lau
- Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA.,Cancer Biology Ph.D. Program, University of South Florida, Tampa, Florida, USA.,Molecular Medicine Program, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida, USA
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26
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Wu CH, Inoue T, Nakamura Y, Uni R, Hasegawa S, Maekawa H, Sugahara M, Wada Y, Tanaka T, Nangaku M, Inagi R. Activation of α7 nicotinic acetylcholine receptors attenuates monocyte-endothelial adhesion through FUT7 inhibition. Biochem Biophys Res Commun 2022; 590:89-96. [PMID: 34973535 DOI: 10.1016/j.bbrc.2021.12.094] [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: 12/22/2021] [Accepted: 12/24/2021] [Indexed: 11/02/2022]
Abstract
Cholinergic anti-inflammatory pathway (CAP) describes a neuronal-inflammatory reflex centered on systemic cytokine regulation by α7 nicotinic acetylcholine receptor (α7nAChR) activation of spleen-residue macrophage. However, the CAP mechanism attenuating distal tissue inflammation, inducing a low level of systemic inflammation, is lesser known. In this study, we hypothesized that CAP regulates monocyte accessibility by influencing their adhesion to endothelial cells. Using RNA-seq analysis, we identified that α1,3-Fucosyltransferase 7 (FucT-VII), the enzyme required for processing selectin ligands, was significantly downregulated by α7nAChR agonist among other cell-cell adhesion genes. The α7nAChR agonist inhibited monocytic cell line U-937 binding to P-selectin and adhesion to endothelial cells. Furthermore, α7nAChR agonist selectivity was confirmed by α7nAChR knockdown assays, showing that FUT7 inhibition and adhesion attenuation by the agonist was abolished by siRNA targeting α7nAChR encoding gene. Consistently, FUT7 knockdown inhibited the adhesive properties of U-937 and prevented them to adhere to endothelial cells. Overexpression of FUT7 also abrogated the adhesion attenuation induced by GTS-21 indicating that FUT7 inhibition was sufficient for inhibiting adhesion by α7nAChR activation. Our work demonstrated that α7nAChR activation regulates monocyte adhesion to endothelial cells through FUT7 inhibition, providing a novel insight into the CAP mechanism.
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Affiliation(s)
- Chia-Hsien Wu
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Tsuyoshi Inoue
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Yasuna Nakamura
- Department of Physiology of Visceral Function and Body Fluid, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Rie Uni
- Division of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Sho Hasegawa
- Division of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Hiroshi Maekawa
- Division of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Mai Sugahara
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Youichiro Wada
- Isotope Science Center, The University of Tokyo, Tokyo, Japan
| | - Tetsuhiro Tanaka
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Masaomi Nangaku
- Division of Nephrology and Endocrinology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
| | - Reiko Inagi
- Division of CKD Pathophysiology, The University of Tokyo Graduate School of Medicine, Tokyo, Japan
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27
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Sołkiewicz K, Krotkiewski H, Jędryka M, Czekański A, Kratz EM. The Alterations of Serum IgG Fucosylation as a Potential Additional New Diagnostic Marker in Advanced Endometriosis. J Inflamm Res 2022; 15:251-266. [PMID: 35058701 PMCID: PMC8764169 DOI: 10.2147/jir.s341906] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 12/03/2021] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND Endometriosis is an inflammatory disease leading to the growth of endometrial-like tissue outside of the uterus, which affects approximately 10% of young women of reproductive potential. The diagnosis of this disease is difficult, often invasive and time-consuming, therefore non-invasive diagnostic methods are strongly desirable in endometriosis detection. The aim of our project was to investigate whether any associations exist between the expression of serum IgG fucosylation and advanced stages of endometriosis. We were also interested in whether native serum IgG (s-IgG) fucosylation analysis, without prior IgG isolation, could provide a panel of parameters helpful in non-invasive diagnostics of advanced endometriosis. METHODS IgG fucosylation was examined using a lectin-ELISA test with fucose-specific lectins: AAL and LCA, specific for core fucose α1,6-linked, as well as LTA and UEA which recognize α1,3- and α1,2-linked fucose, respectively. RESULTS ROC curve and cluster analysis showed s-IgG reactivities with the panel of fucose-specific lectins AAL, LCA and LTA. CONCLUSION s-IgG reactivity with the panel of fucose-specific lectins AAL, LCA and LTA can be taken into account as a useful diagnostic and clinical tool to differentiate women with advanced endometriosis. Moreover, it has been shown that the analysis of native IgG fucosylation directly in serum, without prior time-consuming, expensive IgG isolation, is sufficient to distinguish advanced stages of endometriosis from a control group of healthy women.
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Affiliation(s)
- Katarzyna Sołkiewicz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, 50-556, Poland
| | - Hubert Krotkiewski
- Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, 53-114, Poland
| | - Marcin Jędryka
- Department of Oncology, Gynecological Oncology Clinic, Faculty of Medicine, Wroclaw Medical University, Wroclaw, 53-413, Poland
- Department of Oncological Gynecology, Wroclaw Comprehensive Cancer Center, Wroclaw, 53-413, Poland
| | - Andrzej Czekański
- Department of Oncology, Gynecological Oncology Clinic, Faculty of Medicine, Wroclaw Medical University, Wroclaw, 53-413, Poland
- Department of Oncological Gynecology, Wroclaw Comprehensive Cancer Center, Wroclaw, 53-413, Poland
| | - Ewa Maria Kratz
- Department of Laboratory Diagnostics, Division of Laboratory Diagnostics, Faculty of Pharmacy, Wroclaw Medical University, Wroclaw, 50-556, Poland
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28
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Mulari S, Eskin A, Lampinen M, Nummi A, Nieminen T, Teittinen K, Ojala T, Kankainen M, Vento A, Laurikka J, Kupari M, Harjula A, Tuncbag N, Kankuri E. Ischemic Heart Disease Selectively Modifies the Right Atrial Appendage Transcriptome. Front Cardiovasc Med 2021; 8:728198. [PMID: 34926599 PMCID: PMC8674465 DOI: 10.3389/fcvm.2021.728198] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 11/01/2021] [Indexed: 11/20/2022] Open
Abstract
Background: Although many pathological changes have been associated with ischemic heart disease (IHD), molecular-level alterations specific to the ischemic myocardium and their potential to reflect disease severity or therapeutic outcome remain unclear. Currently, diagnosis occurs relatively late and evaluating disease severity is largely based on clinical symptoms, various imaging modalities, or the determination of risk factors. This study aims to identify IHD-associated signature RNAs from the atrial myocardium and evaluate their ability to reflect disease severity or cardiac surgery outcomes. Methods and Results: We collected right atrial appendage (RAA) biopsies from 40 patients with invasive coronary angiography (ICA)-positive IHD undergoing coronary artery bypass surgery and from 8 patients ICA-negative for IHD (non-IHD) undergoing valvular surgery. Following RNA sequencing, RAA transcriptomes were analyzed against 429 donors from the GTEx project without cardiac disease. The IHD transcriptome was characterized by repressed RNA expression in pathways for cell-cell contacts and mitochondrial dysfunction. Increased expressions of the CSRNP3, FUT10, SHD, NAV2-AS4, and hsa-mir-181 genes resulted in significance with the complexity of coronary artery obstructions or correlated with a functional cardiac benefit from bypass surgery. Conclusions: Our results provide an atrial myocardium-focused insight into IHD signature RNAs. The specific gene expression changes characterized here, pave the way for future disease mechanism-based identification of biomarkers for early detection and treatment of IHD.
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Affiliation(s)
- Severi Mulari
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Arda Eskin
- Department of Health Informatics, Graduate School of Informatics, Middle East Technical University (METU), Ankara, Turkey
| | - Milla Lampinen
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Department of Oral and Maxillofacial Diseases, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Annu Nummi
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Tuomo Nieminen
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Kari Teittinen
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Teija Ojala
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
| | - Matti Kankainen
- Research Programs Unit, University of Helsinki, Helsinki, Finland
| | - Antti Vento
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Jari Laurikka
- Department of Cardiothoracic Surgery, Heart Center, Tampere University Hospital, Tampere, Finland
- Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
| | - Markku Kupari
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Ari Harjula
- Heart and Lung Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
| | - Nurcan Tuncbag
- Department of Health Informatics, Graduate School of Informatics, Middle East Technical University (METU), Ankara, Turkey
- Department of Chemical and Biological Engineering, College of Engineering, Koc University, Istanbul, Turkey
- School of Medicine, Koc University, Istanbul, Turkey
| | - Esko Kankuri
- Department of Pharmacology, Faculty of Medicine, University of Helsinki, Helsinki, Finland
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Systematic review of robust experimental models of rheumatoid arthritis for basic research. DIGITAL CHINESE MEDICINE 2021. [DOI: 10.1016/j.dcmed.2021.12.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
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Mueller AL, Payandeh Z, Mohammadkhani N, Mubarak SMH, Zakeri A, Alagheband Bahrami A, Brockmueller A, Shakibaei M. Recent Advances in Understanding the Pathogenesis of Rheumatoid Arthritis: New Treatment Strategies. Cells 2021; 10:cells10113017. [PMID: 34831240 PMCID: PMC8616543 DOI: 10.3390/cells10113017] [Citation(s) in RCA: 111] [Impact Index Per Article: 27.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2021] [Revised: 11/03/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023] Open
Abstract
Rheumatoid arthritis (RA) is considered a chronic systemic, multi-factorial, inflammatory, and progressive autoimmune disease affecting many people worldwide. While patients show very individual courses of disease, with RA focusing on the musculoskeletal system, joints are often severely affected, leading to local inflammation, cartilage destruction, and bone erosion. To prevent joint damage and physical disability as one of many symptoms of RA, early diagnosis is critical. Auto-antibodies play a pivotal clinical role in patients with systemic RA. As biomarkers, they could help to make a more efficient diagnosis, prognosis, and treatment decision. Besides auto-antibodies, several other factors are involved in the progression of RA, such as epigenetic alterations, post-translational modifications, glycosylation, autophagy, and T-cells. Understanding the interplay between these factors would contribute to a deeper insight into the causes, mechanisms, progression, and treatment of the disease. In this review, the latest RA research findings are discussed to better understand the pathogenesis, and finally, treatment strategies for RA therapy are presented, including both conventional approaches and new methods that have been developed in recent years or are currently under investigation.
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Affiliation(s)
- Anna-Lena Mueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; (A.-L.M.); (A.B.)
| | - Zahra Payandeh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz 5166-15731, Iran;
| | - Niloufar Mohammadkhani
- Department of Clinical Biochemistry, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran;
- Children’s Medical Center, Network of Immunity in Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran 1419733151, Iran
| | - Shaden M. H. Mubarak
- Department of Clinical Laboratory Science, Faculty of Pharmacy, University of Kufa, Najaf 1967365271, Iraq;
| | - Alireza Zakeri
- Department of Biology Sciences, Shahid Rajaee Teacher Training University, Tehran 1678815811, Iran;
| | - Armina Alagheband Bahrami
- Department of Biotechnology, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran 1985717443, Iran;
| | - Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; (A.-L.M.); (A.B.)
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, 80336 Munich, Germany; (A.-L.M.); (A.B.)
- Correspondence: ; Tel.: +49-89-2180-72624
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Messina A, Palmigiano A, Tosto C, Romeo DA, Sturiale L, Garozzo D, Leonardi A. Tear N-glycomics in vernal and atopic keratoconjunctivitis. Allergy 2021; 76:2500-2509. [PMID: 33583051 DOI: 10.1111/all.14775] [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: 10/04/2020] [Revised: 12/08/2020] [Accepted: 12/23/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE Tear fluid N-Glycome from patients affected with vernal (VKC) and atopic keratoconjunctivitis (AKC) was investigated to identify specific changes in tears and to recognize possible glyco-biomarkers. METHODS The analysis of the N-glycans was performed using matrix-assisted laser desorption ionization mass spectrometry on single tear samples. Tears from control normal subjects (CTRL), VKC and AKC patients were processed and treated with peptide N-glycosidase F (PNGase F) to deglycosylate N-glycoproteins. Released N-glycans were purified, permethylated, and analyzed by matrix-assisted laser desorption/ionization-time of flight mass spectrometry and tandem mass spectrometry (MALDI-TOF MS and MALDI-TOF MS/MS). RESULTS More than 150 complex N-glycans, including highly fucosylated biantennary, triantennary, tetra-antennary, and bisecting species, were observed in our spectra. Three distinct patterns for CTRL, VKC, and AKC patients were identified in terms of relative intensities for some N-glycans structures. Major variations involved bisecting and hyperfucosylated glycoforms. The most intense ions were associated with species at m/z 1907.0 (asialo, agalacto, bisected, biantennary structure-NGA2B) in CTRL MS profiles, at m/z 2605.3 and 2966.5 in VKC, and at m/z 2792.4 in AKC corresponding to a well-known biantennary, disialylated N-glycan. Several peaks were associated with structures bearing one or two Lewis X epitopes. Structures were confirmed by MS/MS analysis. Quantitative differences among the three groups were statistically significant. CONCLUSIONS Tear MS profiles are rich in specific glycoforms, particularly those with a high fucosylation degree, indicating both core and peripheral decoration. Tear N-glycome analysis provided important information for a better comprehension of VKC and AKC alterations at the molecular level.
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Affiliation(s)
- Angela Messina
- Consiglio Nazionale delle Ricerche (CNR) Istituto per i Polimeri Compositi e Biomateriali (IPCB) Catania Catania Italy
| | - Angelo Palmigiano
- Consiglio Nazionale delle Ricerche (CNR) Istituto per i Polimeri Compositi e Biomateriali (IPCB) Catania Catania Italy
| | - Claudia Tosto
- Consiglio Nazionale delle Ricerche (CNR) Istituto per i Polimeri Compositi e Biomateriali (IPCB) Catania Catania Italy
| | - Donata Agata Romeo
- Consiglio Nazionale delle Ricerche (CNR) Istituto per i Polimeri Compositi e Biomateriali (IPCB) Catania Catania Italy
| | - Luisa Sturiale
- Consiglio Nazionale delle Ricerche (CNR) Istituto per i Polimeri Compositi e Biomateriali (IPCB) Catania Catania Italy
| | - Domenico Garozzo
- Consiglio Nazionale delle Ricerche (CNR) Istituto per i Polimeri Compositi e Biomateriali (IPCB) Catania Catania Italy
| | - Andrea Leonardi
- Department of Neuroscience, Ophthalmology Unit University of Padua Padua Italy
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Inhibition of Aberrant α(1,2)-Fucosylation at Ocular Surface Ameliorates Dry Eye Disease. Int J Mol Sci 2021; 22:ijms22157863. [PMID: 34360627 PMCID: PMC8346094 DOI: 10.3390/ijms22157863] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Revised: 07/17/2021] [Accepted: 07/21/2021] [Indexed: 12/12/2022] Open
Abstract
Fucosylation is involved in a wide range of biological processes from cellular adhesion to immune regulation. Although the upregulation of fucosylated glycans was reported in diseased corneas, its implication in ocular surface disorders remains largely unknown. In this study, we analyzed the expression of a fucosylated glycan on the ocular surface in two mouse models of dry eye disease (DED), the NOD.B10.H2b mouse model and the environmental desiccating stress model. We furthermore investigated the effects of aberrant fucosylation inhibition on the ocular surface and DED. Results demonstrated that the level of type 2 H antigen, an α(1,2)-fucosylated glycan, was highly increased in the cornea and conjunctiva both in NOD.B10.H2b mice and in BALB/c mice subjected to desiccating stress. Inhibition of α(1,2)-fucosylation by 2-deoxy-D-galactose (2-D-gal) reduced corneal epithelial defects and increased tear production in both DED models. Moreover, 2-D-gal treatment suppressed the levels of inflammatory cytokines in the ocular surface and the percentages of IFN-γ+CD4+ cells in draining lymph nodes, whereas it did not affect the number of conjunctival goblet cells, the MUC5AC level or the meibomian gland area. Together, the findings indicate that aberrant fucosylation underlies the pathogenesis of DED and may be a novel target for DED therapy.
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Sparstolonin B Exerts Therapeutic Effects on Collagen-Induced Arthritis by Inhibiting the NLRP3 Inflammasome and Reducing the Activity of α1,3-Fucosyltransferase. Mediators Inflamm 2021. [DOI: 10.1155/2021/8145412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Objective. To explore the role of α1,3-fucosyltransferase in the mediation of rheumatoid arthritic inflammation, the protective effect of Sparstolonin B on rheumatoid arthritis (RA), and the mechanisms that regulate the NLRP3 inflammasome. Methods. Forty, weighing from 260-300 g, male Sprague-Dawley rats were randomly divided into the following groups: a sham operation group (Sham group), a rheumatoid arthritis model group (RA group), an RA+Sparstolonin B treatment group (RAS group), an RA+Iguratimod group (RAI group), and an RA+SsnB+NLRP3 inflammasome activator (Nigericin) group (RASN group); ten animals were allocated to each group. We determined the arthritis index for each group of rats, and pathological changes were evaluated by hematoxylin-eosin staining. We also used ELISAs to determine the serum levels of IL-17, IL-6, TNF-α, TGF-β, IL-18, and IL-1β. TUNEL staining was used to investigate apoptosis in synovial cells. IF was used to detect the release of ROS, ASC formation, and the expression levels of FucT-V and NLRP3. Western blotting was used to detect the protein expression levels of Bc1-2, Bax, TLR4, MYD88, NF-κB, pro-caspase-1, NLRP3, FucT-V, E-Selectin, and P-Selectin. We also performed in vitro experiments with Sparstolonin B and detected changes in 1,3-fucosyltransferase activity by ELISA. The pyroptosis-related phenotype, including ASC, was identified by immunofluorescence, while levels of NLRP-3, pro-IL-1, and pro-caspase-1 were detected by western blotting. Results. Sparstolonin B was showed to alleviate joint swelling in RA rats, inhibited inflammatory cell infiltration and the release of ROS, reduced damage caused by oxidative stress, and suppressed the rate of apoptosis in synovial cells. The administration of Sparstolonin B inhibited the secretion of IL-17 from Th17 cells and triggered the secretion of TGF-β from Treg cells, thus leading to the reduced expression of TLR4, MyD88, and NF-κB, and the suppression of TNF-α secretion. Moreover, Sparstolonin B downregulated the expression of NLRP3, inhibited ASC formation in vivo and in vitro, and reduced the levels of IL-18 and IL-1β. The expression levels of FucT-V, E-Selectin, and P-Selectin were also inhibited. Interestingly, these protective effects of Sparstolonin B could be blocked in RA rats by inhibiting the activation of the NLRP3 inflammasome. Conclusion. Sparstolonin B improved inflammatory responses and oxidative stress by inhibiting the NLRP3 inflammasome, inhibiting the expression of FucT-V and downregulating the TLR4/MYD88/NF-𝜅B signaling pathway in order to rescue RA.
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Loong JH, Wong TL, Tong M, Sharma R, Zhou L, Ng KY, Yu HJ, Li CH, Man K, Lo CM, Guan XY, Lee TK, Yun JP, Ma SK. Glucose deprivation-induced aberrant FUT1-mediated fucosylation drives cancer stemness in hepatocellular carcinoma. J Clin Invest 2021; 131:143377. [PMID: 33878034 PMCID: PMC8159685 DOI: 10.1172/jci143377] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 04/14/2021] [Indexed: 12/22/2022] Open
Abstract
Rapidly growing tumors often experience hypoxia and nutrient (e.g., glucose) deficiency because of poor vascularization. Tumor cells respond to the cytotoxic effects of such stresses by inducing molecular adaptations that promote clonal selection of a more malignant tumor-initiating cell phenotype, especially in the innermost tumor regions. Here, we report a regulatory mechanism involving fucosylation by which glucose restriction promotes cancer stemness to drive drug resistance and tumor recurrence. Using hepatocellular carcinoma (HCC) as a model, we showed that restricted glucose availability enhanced the PERK/eIF2α/ATF4 signaling axis to drive fucosyltransferase 1 (FUT1) transcription via direct binding of ATF4 to the FUT1 promoter. FUT1 overexpression is a poor prognostic indicator for HCC. FUT1 inhibition could mitigate tumor initiation, self-renewal, and drug resistance. Mechanistically, we demonstrated that CD147, ICAM-1, EGFR, and EPHA2 are glycoprotein targets of FUT1, in which such fucosylation would consequently converge on deregulated AKT/mTOR/4EBP1 signaling to drive cancer stemness. Treatment with an α-(1,2)-fucosylation inhibitor sensitized HCC tumors to sorafenib, a first-line molecularly targeted drug used for advanced HCC patients, and reduced the tumor-initiating subset. FUT1 overexpression and/or CD147, ICAM-1, EGFR, and EPHA2 fucosylation may be good prognostic markers and therapeutic targets for cancer patients.
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Affiliation(s)
- Jane H.C. Loong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
| | - Tin-Lok Wong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
| | - Man Tong
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
- State Key Laboratory of Liver Research
| | - Rakesh Sharma
- Proteomics and Metabolomics Core Facility, Centre for PanorOmic Sciences, Li Ka Shing Faculty of Medicine, and
| | - Lei Zhou
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
| | - Kai-Yu Ng
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
| | - Hua-Jian Yu
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
| | - Chi-Han Li
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
| | - Kwan Man
- State Key Laboratory of Liver Research
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China
- The University of Hong Kong – Shenzhen Hospital, Shenzhen, China
| | - Chung-Mau Lo
- State Key Laboratory of Liver Research
- Department of Surgery, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China
- The University of Hong Kong – Shenzhen Hospital, Shenzhen, China
| | - Xin-Yuan Guan
- State Key Laboratory of Liver Research
- The University of Hong Kong – Shenzhen Hospital, Shenzhen, China
- Department of Clinical Oncology, Queen Mary Hospital, The University of Hong Kong, Hong Kong SAR, China
| | - Terence K. Lee
- Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hong Kong SAR, China
| | - Jing-Ping Yun
- Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou, China
| | - Stephanie K.Y. Ma
- School of Biomedical Sciences, Li Ka Shing Faculty of Medicine
- State Key Laboratory of Liver Research
- The University of Hong Kong – Shenzhen Hospital, Shenzhen, China
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Dietary Fucose Affects Macrophage Polarization and Reproductive Performance in Mice. Nutrients 2021; 13:nu13030855. [PMID: 33807914 PMCID: PMC8001062 DOI: 10.3390/nu13030855] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 12/30/2022] Open
Abstract
Intestinal mucus protects epithelial and immune cells from the gut resident microorganisms, and provides growth-promoting factors as mucus-derived O-glycans for beneficial bacteria. A lack of intestinal protective mucus results in changes in the commensal microflora composition, mucosal immune system reprogramming, and inflammation. Previous work has shown that fucose, the terminal glycan chain component of the intestinal glycoprotein Mucin2, and fucoidan polysaccharides have an anti-inflammatory effect in some mouse models of colitis. This study evaluates the effect of fucose on reproductive performance in heterozygous mutant Muc2 female mice. We found that even though Muc2+/− females are physiologically indistinguishable from C57Bl/6 mice, they have a significantly reduced reproductive performance upon dietary fucose supplementation. Metagenomic analysis reveals that the otherwise healthy wild-type siblings of Muc2−/− animals have reduced numbers of some of the intestinal commensal bacterial species, compared to C57BL/6 mice. We propose that the changes in beneficial microflora affect the immune status in Muc2+/− mice, which causes implantation impairment. In accordance with this hypothesis, we find that macrophage polarization during pregnancy is impaired in Muc2+/− females upon addition of fucose. Metabolic profiling of peritoneal macrophages from Muc2+/− females reveals their predisposition towards anaerobic glycolysis in favor of oxidative phosphorylation, compared to C57BL/6-derived cells. In vitro experiments on phagocytosis activity and mitochondrial respiration suggest that fucose affects oxidative phosphorylation in a genotype-specific manner, which might interfere with implantation depending on the initial status of macrophages. This hypothesis is further confirmed in BALB/c female mice, where fucose caused pregnancy loss and opposed implantation-associated M2 macrophage polarization. Taken together, these data suggest that intestinal microflora affects host immunity and pregnancy outcome. At the same time, dietary fucose might act as a differential regulator of macrophage polarization during implantation, depending on the immune status of the host.
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Xiao J, Wang R, Cai X, Ye Z. Coupling of Co-expression Network Analysis and Machine Learning Validation Unearthed Potential Key Genes Involved in Rheumatoid Arthritis. Front Genet 2021; 12:604714. [PMID: 33643380 PMCID: PMC7905311 DOI: 10.3389/fgene.2021.604714] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2020] [Accepted: 01/04/2021] [Indexed: 12/21/2022] Open
Abstract
Rheumatoid arthritis (RA) is an incurable disease that afflicts 0.5-1.0% of the global population though it is less threatening at its early stage. Therefore, improved diagnostic efficiency and prognostic outcome are critical for confronting RA. Although machine learning is considered a promising technique in clinical research, its potential in verifying the biological significance of gene was not fully exploited. The performance of a machine learning model depends greatly on the features used for model training; therefore, the effectiveness of prediction might reflect the quality of input features. In the present study, we used weighted gene co-expression network analysis (WGCNA) in conjunction with differentially expressed gene (DEG) analysis to select the key genes that were highly associated with RA phenotypes based on multiple microarray datasets of RA blood samples, after which they were used as features in machine learning model validation. A total of six machine learning models were used to validate the biological significance of the key genes based on gene expression, among which five models achieved good performances [area under curve (AUC) >0.85], suggesting that our currently identified key genes are biologically significant and highly representative of genes involved in RA. Combined with other biological interpretations including Gene Ontology (GO) analysis, protein-protein interaction (PPI) network analysis, as well as inference of immune cell composition, our current study might shed a light on the in-depth study of RA diagnosis and prognosis.
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Affiliation(s)
- Jianwei Xiao
- Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Rongsheng Wang
- Department of Rheumatology, Shanghai Guanghua Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai, China
| | - Xu Cai
- Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
| | - Zhizhong Ye
- Department of Rheumatology and Immunology, Shenzhen Futian Hospital for Rheumatic Diseases, Shenzhen, China
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Viladomiu M, Metz ML, Lima SF, Jin WB, Chou L, Guo CJ, Diehl GE, Simpson KW, Scherl EJ, Longman RS. Adherent-invasive E. coli metabolism of propanediol in Crohn's disease regulates phagocytes to drive intestinal inflammation. Cell Host Microbe 2021; 29:607-619.e8. [PMID: 33539767 DOI: 10.1016/j.chom.2021.01.002] [Citation(s) in RCA: 69] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2020] [Revised: 11/29/2020] [Accepted: 01/08/2021] [Indexed: 02/06/2023]
Abstract
Adherent-invasive E. coli (AIEC) are enriched in the intestinal microbiota of patients with Crohn's disease (CD) and promote intestinal inflammation. Yet, how AIEC metabolism of nutrients impacts intestinal homeostasis is poorly defined. Here, we show that AIEC encoding the large subunit of propanediol dehydratase (PduC), which facilitates the utilization of fucose fermentation product 1,2-propanediol, are increased in the microbiome of CD patients and drive AIEC-induced intestinal T cell inflammation. In murine models, CX3CR1+ mononuclear phagocytes (MNP) are required for PduC-dependent induction of T helper 17 (Th17) cells and interleukin-1β (IL-1β) production that leads to AIEC-induced inflammatory colitis. Activation of this inflammatory cascade requires the catalytic activity of PduC to generate propionate, which synergizes with lipopolysaccharide (LPS) to induce IL-1β by MNPs. Disrupting fucose availability limits AIEC-induced propionate production and intestinal inflammation. These findings identify MNPs as metabolic sensors linking AIEC metabolism with intestinal inflammation and identify microbial metabolism as a potential therapeutic target in Crohn's disease treatment.
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Affiliation(s)
- Monica Viladomiu
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Maeva L Metz
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Svetlana F Lima
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Wen-Bing Jin
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Lance Chou
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
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- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Chun-Jun Guo
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA
| | - Gretchen E Diehl
- Immunology Program, Memorial Sloan Kettering Cancer Center, New York, NY 10021, USA
| | - Kenneth W Simpson
- College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA
| | - Ellen J Scherl
- Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA
| | - Randy S Longman
- Jill Roberts Institute for IBD Research, Weill Cornell Medicine, New York, NY 10021, USA; Jill Roberts Center for IBD, Division of Gastroenterology and Hepatology, Department of Medicine, Weill Cornell Medicine, New York, NY 10021, USA.
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Yang L, Zhang Q, Lin L, Xu Y, Huang Y, Hu Z, Wang K, Zhang C, Yang P, Yu H. Microarray investigation of glycan remodeling during macrophage polarization reveals α2,6 sialic acid as an anti-inflammatory indicator. Mol Omics 2021; 17:565-571. [PMID: 34002197 DOI: 10.1039/d0mo00192a] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Glycosylation is a widely occurring posttranslational modification. Here, we applied a quick, convenient and high-throughput strategy (lectin array) to investigate the variation in glycans on different macrophage subtypes derived from THP-1 and RAW264.7 cells. For THP-1 cells, there were more significant differences in the glycan on M2 macrophages compared to the other two subtypes. In contrast, M1 macrophages exhibited more significant glycan remodeling than the other subtypes for the RAW264.7 cell line. The response of the lectins which recogonize the N-glycan and α2,6 sialic acid was higher during polarization into anti-inflammatory phase (THP-1 derived M2 subtypes), and lower in pro-inflammatory phase (RAW264.7 M1 subtypes). The regulation of several α2,6 sialyltransferase genes was coincident with the regulation of the α2,6 sialic acid on the two cell lines. The lectin response and glycosyltranferase gene expression confirmed that α2,6 sialic acid showed higher expression in the anti-inflammatory phase. This indicated that α2,6 sialic acid was a potential indicator for the anti-inflammatory response.
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Affiliation(s)
- Lujie Yang
- Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.
| | - Quanqing Zhang
- Department of Chemistry and Environmental Toxicology Graduate Program, University of California, Riverside, California 92521-0403, USA
| | - Ling Lin
- Xiamen Cardiovascular Hospital, Xiamen University, Xiamen 361008, China
| | - Ying Xu
- Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.
| | - Yuanyu Huang
- Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.
| | - Zuojian Hu
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Ke Wang
- Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.
| | - Cuiping Zhang
- Department of Clinical Laboratory, First Affiliated Hospital of Guangxi Medical University, Nanning 530021, Guangxi, China
| | - Pengyuan Yang
- Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.
| | - Hongxiu Yu
- Institutes of Biomedical Sciences & Shanghai Stomatological Hospital, Fudan University, Shanghai, 200032, China.
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Dai Y, Hartke R, Li C, Yang Q, Liu JO, Wang LX. Synthetic Fluorinated l-Fucose Analogs Inhibit Proliferation of Cancer Cells and Primary Endothelial Cells. ACS Chem Biol 2020; 15:2662-2672. [PMID: 32930566 PMCID: PMC10901565 DOI: 10.1021/acschembio.0c00228] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
Fucosylation is one of the most prevalent modifications on N- and O-glycans of glycoproteins, and it plays an important role in various cellular processes and diseases. Small molecule inhibitors of fucosylation have shown promise as therapeutic agents for sickle cell disease, arthritis, and cancer. We describe here the design and synthesis of a panel of fluorinated l-fucose analogs bearing fluorine atoms at the C2 and/or C6 positions of l-fucose as metabolic fucosylation inhibitors. Preliminary study of their effects on cell proliferation revealed that the 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6) showed significant inhibitory activity against proliferation of human colon cancer cells and human umbilical vein endothelial cells. In contrast, the previously reported 2-deoxy-2-fluoro-l-fucose (1) had no apparent effects on proliferations of all the cell lines tested. To understand the mechanism of cell proliferation inhibition by the fluorinated l-fucose analogs, we performed chemoenzymatic synthesis of the corresponding GDP-fluorinated l-fucose analogs and tested their inhibitory activities against the mammalian α1,6-fucosyltransferase (FUT8). Interestingly, the corresponding GDP derivatives of 6,6-difluoro-l-fucose (3) and 6,6,6-trifluoro-l-fucose (6), which are the stronger proliferation inhibitors, showed much weaker inhibitory activity against FUT8 than that of the 2-deoxy-2-fluoro-l-fucose (1). These results suggest that FUT8 is not the major target of the 6-fluorinated fucose analogs (3 and 6). Instead, other factors, such as the key enzymes involved in the de novo GDP-fucose biosynthetic pathway and/or other fucosyltransferases involved in the biosynthesis of tumor-associated glyco-epitopes are most likely the targets of the fluorinated l-fucose analogs to achieve cell proliferation inhibition. To our knowledge, this is the first comparative study of various fluorinated l-fucose analogs for suppressing the proliferation of human cancer and primary endothelial cells required for angiogenesis.
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Affiliation(s)
- Yuanwei Dai
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
| | - Ruth Hartke
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Chao Li
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
| | - Qiang Yang
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
| | - Jun O Liu
- Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, United States
| | - Lai-Xi Wang
- Department of Chemistry and Biochemistry, University of Maryland, College Park, Maryland 20742, United States
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40
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Perakakis N, Stefanakis K, Mantzoros CS. The role of omics in the pathophysiology, diagnosis and treatment of non-alcoholic fatty liver disease. Metabolism 2020; 111S:154320. [PMID: 32712221 PMCID: PMC7377759 DOI: 10.1016/j.metabol.2020.154320] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2020] [Revised: 07/15/2020] [Accepted: 07/18/2020] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a multifaceted metabolic disorder, whose spectrum covers clinical, histological and pathophysiological developments ranging from simple steatosis to non-alcoholic steatohepatitis (NASH) and liver fibrosis, potentially evolving into cirrhosis, hepatocellular carcinoma and liver failure. Liver biopsy remains the gold standard for diagnosing NAFLD, while there are no specific treatments. An ever-increasing number of high-throughput Omics investigations on the molecular pathobiology of NAFLD at the cellular, tissue and system levels produce comprehensive biochemical patient snapshots. In the clinical setting, these applications are considerably enhancing our efforts towards obtaining a holistic insight on NAFLD pathophysiology. Omics are also generating non-invasive diagnostic modalities for the distinct stages of NAFLD, that remain though to be validated in multiple, large, heterogenous and independent cohorts, both cross-sectionally as well as prospectively. Finally, they aid in developing novel therapies. By tracing the flow of information from genomics to epigenomics, transcriptomics, proteomics, metabolomics, lipidomics and glycomics, the chief contributions of these techniques in understanding, diagnosing and treating NAFLD are summarized herein.
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Affiliation(s)
- Nikolaos Perakakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA..
| | - Konstantinos Stefanakis
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
| | - Christos S Mantzoros
- Department of Internal Medicine, Boston VA Healthcare system and Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA
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41
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Kim SJ, Chang HJ, Volin MV, Umar S, Van Raemdonck K, Chevalier A, Palasiewicz K, Christman JW, Volkov S, Arami S, Maz M, Mehta A, Zomorrodi RK, Fox DA, Sweiss N, Shahrara S. Macrophages are the primary effector cells in IL-7-induced arthritis. Cell Mol Immunol 2020; 17:728-740. [PMID: 31197255 PMCID: PMC7331600 DOI: 10.1038/s41423-019-0235-z] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 04/10/2019] [Indexed: 12/16/2022] Open
Abstract
Synovial macrophages are crucial in the development of joint inflammation and bone damage; however, the pathways that control macrophage remodeling in inflammatory M1 cells or bone-eroding osteoclasts are not fully understood. We determined that elevated IL-7R/CD127 expression is the hallmark of rheumatoid arthritis (RA) M1 macrophages and that these cells are highly responsive to interleukin-7 (IL-7)-driven osteoclastogenesis. We established that lipopolysaccharide (LPS), interferon-γ (IFNγ), and tumor necrosis factor-α (TNFα), the classic M1 macrophage mediators, enhance IL-7R expression in RA and murine macrophages. The local expression of IL-7 provokes arthritis, predominantly through escalating the number of F480+iNOS+ cells rather than CD3+ T cells. Ectopic LPS injection stabilizes IL-7-induced arthritis by increasing myeloid IL-7R expression, in part via IFNγ induction. Hence, in RAG-/- mice, IL-7-mediated arthritis is suppressed because of the reduction in myeloid IL-7R expression due to the lack of IFNγ. Moreover, the amelioration of IL-7-induced arthritis by anti-TNF therapy is due to a decrease in the number of cells in the unique F480+iNOS+IL-7R+CCL5+ subset, with no impact on the F480+Arginase+ cell or CD3+ T cell frequency. Consistent with the preclinical findings, the findings of a phase 4 study performed with RA patients following 6 months of anti-TNF therapy revealed that IL-7R expression was reduced without affecting the levels of IL-7. This study shifts the paradigm by discovering that IL-7-induced arthritis is dependent on F480+iNOS+IL-7R+CCL5+ cell function, which activates TH-1 cells to amplify myeloid IL-7R expression and disease severity.
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Affiliation(s)
- Seung-Jae Kim
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Huan J Chang
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Michael V Volin
- Department of Microbiology and Immunology, Chicago College of Osteopathic Medicine, Midwestern University, Downers Grove, IL, 60515, USA
| | - Sadiq Umar
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Katrien Van Raemdonck
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Aimee Chevalier
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Karol Palasiewicz
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - John W Christman
- Pulmonary, Critical Care and Sleep Medicine, Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, Columbus, OH, 43210, USA
| | - Suncica Volkov
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Shiva Arami
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Mehrdad Maz
- Division of Allergy, Clinical Immunology and Rheumatology, The University of Kansas Medical Center, Kansas City, KS, 66160, USA
| | - Anjali Mehta
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Ryan K Zomorrodi
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - David A Fox
- Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI, 481096, USA
| | - Nadera Sweiss
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA
| | - Shiva Shahrara
- Division of Rheumatology, Jesse Brown VA, Medical Center, Chicago, IL, 60612, USA.
- Department of Medicine, Division of Rheumatology, University of Illinois at Chicago, Chicago, IL, 60612, USA.
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Nowak B, Śróttek M, Ciszek-Lenda M, Skałkowska A, Gamian A, Górska S, Marcinkiewicz J. Exopolysaccharide from Lactobacillus rhamnosus KL37 Inhibits T Cell-dependent Immune Response in Mice. Arch Immunol Ther Exp (Warsz) 2020; 68:17. [PMID: 32448979 PMCID: PMC7246254 DOI: 10.1007/s00005-020-00581-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 05/10/2020] [Indexed: 01/06/2023]
Abstract
Exopolysaccharides (EPSs), major components of the bacterial biofilm, display strong strain-specific immunomodulatory properties. Previously, we have shown that crude EPS derived from Lactobacillus rhamnosus KL37 depresses the production of arthritogenic anti-collagen IgG and ameliorates collagen-induced arthritis (CIA) in DBA/1 mice, when lipopolysaccharide (LPS) was used as adjuvant. In this study, we used highly purified EPS from L. rhamnosus KL37 (EPS-37) to verify its anti-inflammatory properties and the ability to suppress T cell-dependent humoral response. We have employed the model of active CIA, in which mice immunized with type II collagen (CII) along with LPS were treated with pure EPS-37. Intravenous administration of purified EPS-37 markedly ameliorated arthritis and reduced CII-specific antibody production. EPS-37 injected subcutaneously reduced the clinical symptoms of CIA but without the reduction of arthritogenic antibodies. In addition, the effect of EPS-37 on T-cell functions was tested ex vivo and in vitro. EPS-37 inhibited the in vitro proliferation of T cells activated both in vivo (CII immunization) and in vitro (antigen/mitogen), and markedly reduced the production of interferon (IFN)-γ. These results together with other reports suggest that anti-inflammatory potential of EPS-37 depends on its ability to inhibit either one or the other or both possible inflammatory signaling pathways. Namely, Th1 → IFN-γ → M1 inflammatory macrophages → arthritis and/or Th1 → IFN-γ → B cells → arthritogenic antibodies → arthritis. We suggest that L. rhamnosus KL37 EPS might be utilized to control T cell-dependent immune responses in various inflammatory diseases. However, the most effective route of EPS-37 administration needs to be tailored for a given disorder.
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Affiliation(s)
- Bernadeta Nowak
- Department of Immunology, Jagiellonian University Medical College, Czysta 18, 31-121, Kraków, Poland
| | - Małgorzata Śróttek
- Department of Immunology, Jagiellonian University Medical College, Czysta 18, 31-121, Kraków, Poland
| | - Marta Ciszek-Lenda
- Department of Immunology, Jagiellonian University Medical College, Czysta 18, 31-121, Kraków, Poland
| | - Anna Skałkowska
- Department of Immunology, Jagiellonian University Medical College, Czysta 18, 31-121, Kraków, Poland
| | - Andrzej Gamian
- Laboratory of Medical Microbiology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Sabina Górska
- Laboratory of Microbiome Immunology, Ludwik Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Janusz Marcinkiewicz
- Department of Immunology, Jagiellonian University Medical College, Czysta 18, 31-121, Kraków, Poland.
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Kim KW, Ryu JS, Ko JH, Kim JY, Kim HJ, Lee HJ, Oh JH, Chung JH, Oh JY. FUT1 deficiency elicits immune dysregulation and corneal opacity in steady state and under stress. Cell Death Dis 2020; 11:285. [PMID: 32332708 PMCID: PMC7181665 DOI: 10.1038/s41419-020-2489-x] [Citation(s) in RCA: 5] [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: 01/03/2020] [Revised: 04/09/2020] [Accepted: 04/10/2020] [Indexed: 11/18/2022]
Abstract
Fucosylation is a biological process that plays a critical role in multiple cellular functions from cell adhesion to immune regulation. Fucosyltransferases (FUTs) mediate fucosylation, and dysregulation of genes encoding FUTs is associated with various diseases. FUT1 and its fucosylated products are expressed in the ocular surface and ocular adnexa; however, the role of FUT1 in the ocular surface health and disease is yet unclear. Here, we investigated the effects of FUT1 on the ocular surface in steady-state conditions with age and under desiccating stress using a Fut1 knockout (KO) mouse model. We found that corneal epithelial defects and stromal opacity developed in Fut1 KO mice. Also, inflammatory responses in the ocular surface and Th1 cell activation in ocular draining lymph nodes (DLNs) were upregulated. Desiccating stress further aggravated Th1 cell-mediated immune responses in DLNs, lacrimal gland, and ocular surface in Fut1 KO mice, leading to severe corneal epithelial disruption and opacity. Mixed lymphocyte reaction assays revealed that the activity of splenocytes to stimulate CD4 T-cell proliferation was increased in Fut1 KO mice. Together, these data demonstrate that FUT1 deficiency induces immune dysregulation in the ocular surface and corneal opacity in steady state and under desiccating stress.
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Affiliation(s)
- Kyoung Woo Kim
- Department of Ophthalmology, Chung-Ang University Hospital, Seoul, South Korea
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea
| | - Jin Suk Ryu
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea
| | - Jung Hwa Ko
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea
| | - Jun Yeob Kim
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea
| | - Hyeon Ji Kim
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea
| | - Hyun Ju Lee
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea
| | - Jang-Hee Oh
- Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea
| | - Jin Ho Chung
- Department of Dermatology, Seoul National University College of Medicine, Seoul, South Korea
| | - Joo Youn Oh
- Laboratory of Ocular Regenerative Medicine and Immunology, Seoul Artificial Eye Center, Seoul National University Hospital Biomedical Research Institute, Seoul, South Korea.
- Department of Ophthalmology, Seoul National University College of Medicine, Seoul, South Korea.
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44
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Delannoy C, Huang C, Coddeville B, Chen JY, Mouajjah D, Groux-Degroote S, Harduin-Lepers A, Khoo KH, Guerardel Y, Elass-Rochard E. Mycobacterium bovis BCG infection alters the macrophage N-glycome. Mol Omics 2020; 16:345-354. [PMID: 32270793 DOI: 10.1039/c9mo00173e] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Macrophage glycosylation is essential to initiate the host-immune defense but may also be targeted by pathogens to promote infection. Indeed, the alteration of the cell-surface glycosylation status may affect the binding of lectins involved in cell activation and adhesion. Herein, we demonstrate that infection by M. bovis BCG induces the remodeling of the N-glycomes of both human primary blood monocyte-derived macrophages (MDM) and macrophage-cell line THP1. MALDI-MS based N-glycomic analysis established that mycobacterial infection induced increased synthesis of biantennary and multifucosylated complex type N-glycans. In contrast, infection of macrophages by M. bovis BCG did not modify the glycosphingolipids composition of macrophages. Further nano-LC-MSn glycotope-centric analysis of total N-glycans demonstrated that the increased fucosylation was due to an increased expression of the Lex (Galβ1-4[Fucα1-3]GlcNAc) epitope, also known as stage-specific embryonic antigen-1. Modification of the surface expression of Lex was further confirmed in both MDM and THP-1 cells by FACS analysis using an α1,3-linked fucose specific lectin. Activation with the mycobacterial lipopeptide Pam3Lp19, an agonist of toll-like receptor 2, did not modify the overall fucosylation pattern, which suggests that the infection process is required to modify surface glycosylation. These results pave the way toward the understanding of infection-triggered cell-surface remodeling of macrophages.
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Affiliation(s)
- Clément Delannoy
- Univ. Lille, CNRS UMR 8576, UGSF-Unité de Glycobiologie Structurale et Fonctionnelle, 59 000 Lille, France.
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45
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Yunna C, Mengru H, Lei W, Weidong C. Macrophage M1/M2 polarization. Eur J Pharmacol 2020; 877:173090. [PMID: 32234529 DOI: 10.1016/j.ejphar.2020.173090] [Citation(s) in RCA: 1273] [Impact Index Per Article: 254.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Revised: 03/24/2020] [Accepted: 03/25/2020] [Indexed: 12/12/2022]
Abstract
Macrophages can be affected by a variety of factors to change their phenotype and thus affect their function. Activated macrophages are usually divided into two categories, M1-like macrophages and M2-like macrophages. Both M1 macrophages and M2 macrophages are closely related to inflammatory responses, among which M1 macrophages are mainly involved in pro-inflammatory responses and M2 macrophages are mainly involved in anti-inflammatory responses. Improving the inflammatory environment by modulating the activation state of macrophages is an effective method for the treatment of diseases. In this review, we analyzed the mechanism of macrophage polarization from the tumor microenvironment, nanocarriers, nuclear receptor PPARγ, phagocytosis, NF-κB signaling pathways, and other pathways.
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Affiliation(s)
- Chen Yunna
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui, 230012, China; Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Hu Mengru
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui, 230012, China; Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China
| | - Wang Lei
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui, 230012, China; Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China; Engineering Technology Research Center of Modernized Pharmaceutics, Education Office of Anhui Province, Hefei, Anhui, 230012, China.
| | - Chen Weidong
- College of Pharmacy, Anhui University of Chinese Medicine, Hefei, 230012, China; Anhui Province Key Laboratory of Chinese Medicinal Formula, Hefei, Anhui, 230012, China; Institute of Pharmaceutics, Anhui Academy of Chinese Medicine, Hefei, Anhui, 230012, China; Engineering Technology Research Center of Modernized Pharmaceutics, Education Office of Anhui Province, Hefei, Anhui, 230012, China.
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Shi M, Lin Z, Ye L, Chen X, Zhang W, Zhang Z, Luo F, Liu Y, Shi M. Estrogen receptor-regulated SOCS3 modulation via JAK2/STAT3 pathway is involved in BPF-induced M1 polarization of macrophages. Toxicology 2020; 433-434:152404. [PMID: 32044397 DOI: 10.1016/j.tox.2020.152404] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2019] [Revised: 02/02/2020] [Accepted: 02/06/2020] [Indexed: 12/14/2022]
Abstract
As an alternative to bisphenol A (BPA), bisphenol F (BPF) has been increasingly used in manufacturing various consumer products. Exposured to BPF may lead to imbalanced immune homeostasis, yet the underlying mechanisms have not been fully elucidated. The present study was aimed to investigate the effects of BPF on macrophages and the underlying mechanism in regard to its association with estrogen receptor (ER), janus kinase 2/signal transducer and activator of transcription 3/suppressor of cytokine signaling 3 (JAK2/STAT3/SOCS3) pathway. In this study, after treatment of RAW264.7 macrophages with BPF (0, 5, 10, 20 μM), the macrophage M1 polarization was promoted, and the gene expression of M1 functional markers and pro-inflammatory cytokines was upregulated, which suggested the involvement of a vicious circle associated with chronic inflammation. Moreover, BPF facilitated SOCS3 expression in the cells in a dose-dependent manner, via activation of the JAK2/STAT3 signaling pathway, which may promote the transcription of many pro-inflammatory factors. Additionally, the above effects of BPF were blocked by either JAK2/STAT3 inhibitor AG490 (10 μM) or ER antagonist ICI 182,780 (10 μM). Taken together, the results of this study indicate that BPF promotes macrophage polarization toward pro-inflammatory M1 subtype, through activation of the ER-JAK2/STAT3/SOCS3 signaling pathway. Our finding may provide a new insight into the link between bisphenol exposure and immune dysfunction.
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Affiliation(s)
- Mingjie Shi
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China
| | - Zeheng Lin
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China
| | - Lihe Ye
- Department of Occupational Health Determination, Dongguan Sixth People's Hospital, 523808, Dongguan, China
| | - Xinlin Chen
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China
| | - Wenfeng Zhang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China
| | - Zihan Zhang
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China
| | - Fei Luo
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China
| | - Yungang Liu
- Department of Toxicology, School of Public Health, Southern Medical University, 510515, Guangzhou, China
| | - Ming Shi
- Dongguan Key Laboratory of Environmental Medicine, School of Public Health, Guangdong Medical University, 523808, Dongguan, China.
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Macrophage M1/M2 polarization and rheumatoid arthritis: A systematic review. Autoimmun Rev 2019; 18:102397. [DOI: 10.1016/j.autrev.2019.102397] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2019] [Accepted: 05/03/2019] [Indexed: 02/06/2023]
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Hevey R. Bioisosteres of Carbohydrate Functional Groups in Glycomimetic Design. Biomimetics (Basel) 2019; 4:E53. [PMID: 31357673 PMCID: PMC6784292 DOI: 10.3390/biomimetics4030053] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 07/25/2019] [Accepted: 07/26/2019] [Indexed: 02/07/2023] Open
Abstract
The aberrant presentation of carbohydrates has been linked to a number of diseases, such as cancer metastasis and immune dysregulation. These altered glycan structures represent a target for novel therapies by modulating their associated interactions with neighboring cells and molecules. Although these interactions are highly specific, native carbohydrates are characterized by very low affinities and inherently poor pharmacokinetic properties. Glycomimetic compounds, which mimic the structure and function of native glycans, have been successful in producing molecules with improved pharmacokinetic (PK) and pharmacodynamic (PD) features. Several strategies have been developed for glycomimetic design such as ligand pre-organization or reducing polar surface area. A related approach to developing glycomimetics relies on the bioisosteric replacement of carbohydrate functional groups. These changes can offer improvements to both binding affinity (e.g., reduced desolvation costs, enhanced metal chelation) and pharmacokinetic parameters (e.g., improved oral bioavailability). Several examples of bioisosteric modifications to carbohydrates have been reported; this review aims to consolidate them and presents different possibilities for enhancing core interactions in glycomimetics.
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Affiliation(s)
- Rachel Hevey
- Molecular Pharmacy, Department Pharmaceutical Sciences, University of Basel, Klingelbergstr. 50, 4056 Basel, Switzerland.
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49
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He R, Li Y, Han C, Lin R, Qian W, Hou X. L-Fucose ameliorates DSS-induced acute colitis via inhibiting macrophage M1 polarization and inhibiting NLRP3 inflammasome and NF-kB activation. Int Immunopharmacol 2019; 73:379-388. [PMID: 31132733 DOI: 10.1016/j.intimp.2019.05.013] [Citation(s) in RCA: 99] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2019] [Revised: 05/08/2019] [Accepted: 05/08/2019] [Indexed: 12/12/2022]
Abstract
Previous studies reported that L-fucose had anti-inflammatory effects in respiratory and cutaneous system. However, the effect of L-fucose on colitis and the underlying mechanism is poorly understood. We studied the anti-inflammatory effects of L-fucose on Dextran sulfate sodium (DSS)-induced acute colitis in vivo and on LPS/ATP-induced bone marrow derived macrophages (BMDMs) damage in vitro. Our results show that L-fucose significantly alleviated weight loss and disease activity index (DAI) scores in colitis and reduced the infiltration of macrophages and neutrophils. In addition, L-fucose can inhibit macrophage M1 polarization, inactivate the NLRP3 inflammasome and reduce the release of TNFα, IL1β, IL6 pro-inflammatory cytokines. In vitro studies showed that L-fucose ameliorated cell damage resulting from the administration of LPS with ATP in BMDMs, inhibited NLRP3 inflammasome activation and reduced the release of corresponding pro-inflammatory cytokines. Finally, L-fucose can inhibit the expression of p-NF-kB in vivo and in vitro. Overall, our results show that L-fucose can attenuate colitis by inhibiting macrophage M1 polarization, inhibiting NLRP3 inflammasome and NF-kB activation, and down-regulation of pro-inflammatory cytokines.
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Affiliation(s)
- Ruohang He
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Ying Li
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Chaoqun Han
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Rong Lin
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wei Qian
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaohua Hou
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China.
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Bhattacharya S, Aggarwal A. M2 macrophages and their role in rheumatic diseases. Rheumatol Int 2018; 39:769-780. [DOI: 10.1007/s00296-018-4120-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2018] [Accepted: 08/02/2018] [Indexed: 12/21/2022]
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