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Jung H, Kim YE, Kim EM, Kim KK. Alternative splicing of CHI3L1 regulates protein secretion through conformational changes. Genes Genomics 2025:10.1007/s13258-025-01635-w. [PMID: 40126865 DOI: 10.1007/s13258-025-01635-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2025] [Accepted: 03/12/2025] [Indexed: 03/26/2025]
Abstract
BACKGROUND Alternative splicing (AS) plays a crucial role in regulating protein function through the generation of structurally distinct isoforms. OBJECTIVE We identify a novel splicing event in Chitinase 3-like 1 (CHI3L1) that modulates its secretion through conformational changes. METHODS CHI3L1 alternative splicing was analyzed using the GTEx dataset. The regulation of CHI3L1 splicing was examined in response to THP-1 and BEAS-2B cells using RT-PCR. Structural modeling of CHI3L1 isoforms was conducted with AlphaFold to predict conformational changes caused by exon 8 exclusion. Protein expression and secretion levels of CHI3L1 isoforms were analyzed by Western blotting. RESULTS Analysis of the GTEx dataset revealed tissue-specific regulation of CHI3L1 exon 8, with pronounced exclusion in lung tissue. The splicing pattern of CHI3L1 was dynamically regulated during THP-1 macrophage differentiation and by cell density in lung-derived epithelial BEAS-2B cells, suggesting its responsiveness to cellular context. While both full-length and exon 8-excluded CHI3L1 proteins showed cytoplasmic localization, structural analysis using AlphaFold revealed that exon 8 exclusion significantly altered the orientation of the signal peptide. Consequently, exon 8-excluded CHI3L1 exhibited minimal secretion into the culture medium compared to the full-length protein. CONCLUSION These findings demonstrate that alternative splicing-mediated exclusion of exon 8 serves as a novel regulatory mechanism controlling CHI3L1 secretion through conformational changes, providing new insights into the post-transcriptional regulation of secreted proteins.
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Affiliation(s)
- Haesoo Jung
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Yong-Eun Kim
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, 34134, Republic of Korea
| | - Eun-Mi Kim
- Department of Bio and Environmental Technology, College of Natural Science, Seoul Women's University, Seoul, 01797, Republic of Korea.
| | - Kee K Kim
- Department of Biochemistry, College of Natural Sciences, Chungnam National University, Daejeon, 34134, Republic of Korea.
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2
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Liu Y, Hu W, Yang F, Zou S, Ren H, Zuo Y, Qu L. Chitinase-3-like Protein 1 Reduces the Stability of Atherosclerotic Plaque via Impairing Macrophagic Efferocytosis. J Cardiovasc Transl Res 2025:10.1007/s12265-024-10576-w. [PMID: 39813006 DOI: 10.1007/s12265-024-10576-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 11/25/2024] [Indexed: 01/16/2025]
Abstract
CHI3L1 is strongly associated with atherosclerosis, but its role in macrophages remains unknown. In this study, we observed a significant up-regulation of CHI3L1 in both carotid plaques and serum of symptomatic patients, and demonstrated that CHI3L1 impairs the efferocytosis of macrophages by down-regulating crucial efferocytic mediator MFGE8 through inhibiting ATF2, which binds directly to the enhancer of MFGE8. In human plaques, we observed a negative correlation between CHI3L1 expression and both ATF2 and MFGE8 levels, further proved their involvement in plaque destabilization. Using Ldlr-/- mice with tandem carotid stenosis surgery, we demonstrated that administration of CHI3L1 protein resulted in enlarged atherosclerotic necrotic cores and decreased MFGE8 and ATF2 levels. Conversely, treatment with a CHI3L1 blocking antibody exhibited the opposite trend.In conclusion, CHI3L1 destabilizes atherosclerotic plaque by impairing macrophagic efferocytosis through the down-regulation of ATF2-induced MFGE8 expression. Targeting CHI3L1 may offer a promising therapeutic strategy for the treatment of atherosclerosis.
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Affiliation(s)
- Yandong Liu
- Department of Geriatrics, 905, Hospital of PLA NAVY, Shanghai, China
- Department of Vascular and Endovascular Surgery, Changzheng Hospital, Affiliated to the Naval Medical University, Shanghai, 200003, China
| | - Weilin Hu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital, Affiliated to the Naval Medical University, Shanghai, 200003, China
| | - Futang Yang
- Department of Vascular and Endovascular Surgery, Changzheng Hospital, Affiliated to the Naval Medical University, Shanghai, 200003, China
| | - Sili Zou
- Department of Vascular and Endovascular Surgery, Changzheng Hospital, Affiliated to the Naval Medical University, Shanghai, 200003, China
| | - Huiqiong Ren
- Department of Geriatrics, 905, Hospital of PLA NAVY, Shanghai, China.
| | - Yong Zuo
- Department of Biochemistry and Molecular Cell Biology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Lefeng Qu
- Department of Vascular and Endovascular Surgery, Changzheng Hospital, Affiliated to the Naval Medical University, Shanghai, 200003, China.
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Liu D, Hu X, Ding X, Li M, Ding L. Inflammatory Effects and Regulatory Mechanisms of Chitinase-3-like-1 in Multiple Human Body Systems: A Comprehensive Review. Int J Mol Sci 2024; 25:13437. [PMID: 39769202 PMCID: PMC11678640 DOI: 10.3390/ijms252413437] [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: 10/13/2024] [Revised: 11/29/2024] [Accepted: 12/13/2024] [Indexed: 01/03/2025] Open
Abstract
Chitinase-3-like-1 (Chi3l1), also known as YKL-40 or BRP-39, is a highly conserved mammalian chitinase with a chitin-binding ability but no chitinase enzymatic activity. Chi3l1 is secreted by various cell types and induced by several inflammatory cytokines. It can mediate a series of cell biological processes, such as proliferation, apoptosis, migration, differentiation, and polarization. Accumulating evidence has verified that Chi3l1 is involved in diverse inflammatory conditions; however, a systematic and comprehensive understanding of the roles and mechanisms of Chi3l1 in almost all human body system-related inflammatory diseases is still lacking. The human body consists of ten organ systems, which are combinations of multiple organs that perform one or more physiological functions. Abnormalities in these human systems can trigger a series of inflammatory environments, posing serious threats to the quality of life and lifespan of humans. Therefore, exploring novel and reliable biomarkers for these diseases is highly important, with Chi3l1 being one such parameter because of its physiological and pathophysiological roles in the development of multiple inflammatory diseases. Reportedly, Chi3l1 plays an important role in diagnosing and determining disease activity/severity/prognosis related to multiple human body system inflammation disorders. Additionally, many studies have revealed the influencing factors and regulatory mechanisms (e.g., the ERK and MAPK pathways) of Chi3l1 in these inflammatory conditions, identifying potential novel therapeutic targets for these diseases. In this review, we comprehensively summarize the potential roles and underlying mechanisms of Chi3l1 in inflammatory disorders of the respiratory, digestive, circulatory, nervous, urinary, endocrine, skeletal, muscular, and reproductive systems, which provides a more systematic understanding of Chi3l1 in multiple human body system-related inflammatory diseases. Moreover, this article summarizes potential therapeutic strategies for inflammatory diseases in these systems on the basis of the revealed roles and mechanisms mediated by Chi3l1.
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Affiliation(s)
- Dong Liu
- School of Life Sciences, Yunnan University, Kunming 650500, China;
| | - Xin Hu
- Yunnan Key Laboratory of Soil Erosion Prevention and Green Development, Institute of International Rivers and Ecosecurity, Yunnan University, Kunming 650500, China;
| | - Xiao Ding
- Key Laboratory of Phytochemistry and Natural Medicines, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, China;
| | - Ming Li
- School of Life Sciences, Yunnan University, Kunming 650500, China;
| | - Lei Ding
- School of Life Sciences, Yunnan University, Kunming 650500, China;
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4
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Ozaki K, Terayama Y, Kojima MI, Matsuura T, Ozaki K. Eosinophilic inflammation that begins in the juvenile stage causes hydronephrosis and urothelial cancer in mutant mice. Sci Rep 2024; 14:30217. [PMID: 39633023 PMCID: PMC11618632 DOI: 10.1038/s41598-024-81013-w] [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: 09/12/2024] [Accepted: 11/22/2024] [Indexed: 12/07/2024] Open
Abstract
Obstructive hydronephrosis is caused by various factors such as chronic inflammation and tumors. Eosinophils and chitinase-like proteins (CLPs) are involved in the pathogenesis of hydronephrosis in mice; however, the specific mechanisms remain unknown. In this study, we morphologically analyzed a novel mouse model of obstructive hydronephrosis from onset to progression to clarify the effects of eosinophils and CLP on the development of hydronephrosis and tumorigenesis. The primary change was slight eosinophil infiltration of the ureteropelvic junction, even at 1 week of age, followed by a significant increase in CLP expression in the urothelium at 5 weeks of age, which led to proliferation of the urothelium. At 8 weeks of age, polyps with eosinophilic inflammation and urothelial hyperplasia expressing high levels of CLP formed at the ureteropelvic junction, leading to hydronephrosis. At 60 weeks of age, all mice with hydronephrosis exhibited chronic eosinophilic inflammation and adenomas that progressed to adenocarcinomas with high CLP expression. In summary, inflammation and epithelial proliferation at the ureteropelvic junction began with a single infiltration of eosinophils at the juvenile stage in mice. Eosinophilic inflammation is associated with the development of hydronephrosis and urothelial hyperplasia, which may progress to urothelial adenocarcinoma due to increased CLP expression.
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Affiliation(s)
- Kiyokazu Ozaki
- Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 573-0101, Hirakata, Japan.
| | - Yui Terayama
- Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 573-0101, Hirakata, Japan
| | - Minori Inanaga Kojima
- Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 573-0101, Hirakata, Japan
| | - Tetsuro Matsuura
- Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 573-0101, Hirakata, Japan
| | - Kiyokazu Ozaki
- Laboratory of Pathology, Faculty of Pharmaceutical Sciences, Setsunan University, 573-0101, Hirakata, Japan
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Wang YG, Lin C, Huang M, Fang XL, Chen GH, Ye SN. Overexpression of YKL40,IL-6, IL-8, TNF-α in tonsils and the role of YKL40 in childhood with obstructive sleep apnea syndrome. Sci Rep 2024; 14:26283. [PMID: 39487152 PMCID: PMC11530617 DOI: 10.1038/s41598-024-74402-8] [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: 01/06/2023] [Accepted: 09/25/2024] [Indexed: 11/04/2024] Open
Abstract
To evaluate the levels of YKL40, IL-6(interleukin-6), IL-8(interleukin-8), IL-10(interleukin-10), TNF-α (tumor necrosis factor-α) in OSAS (obstructive sleep apnea syndrome)children and explore the mechanism of YKL40 promoting inflammatory factors overexpression in tonsils. qPCR and ELISA were used to identify the expression of YKL40, IL-6, IL-8, IL-10, and TNF-α in the tonsils of OSAS children. Primary tonsil lymphocytes (PTLCs) were cultured and recombinant human YKL40(rhYKL40)was used to stimulate PTLCs in different concentrations and at different time points. The activation of NF-κB in PTLCs was screened by western blotting. Relative mRNA of YKL40, IL-6, IL-8, TNF-α was over expressed in OSAS-derived tonsil tissue and the levels of YKL40, IL-6, IL-8, and TNF-α was increased in OSAS-derived protein supernatant of tonsil tissue.The relative mRNA expression of IL-6, IL-8 and TNF-α increased under the treatment of YKL40 (100 ng/mmol for 24 h). The phosphorylation of p65 in NF-κB pathway was stimulated in the process. The levels of YKL40, IL-6, IL-8, and TNF-α increases in OSAS children, and YKL40 promotes the overexpression of IL-6, IL-8 and TNF-α in PTLCs via NF-κB pathway. The result implements that inflammation may play an important role in the pathogenesis of OSAS in children.
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Affiliation(s)
- Ying-Ge Wang
- Department of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Fuzhou, 350000, China
- Department of Otorhinolaryngology, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
- Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Chang Lin
- Department of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Fuzhou, 350000, China
- Department of Otorhinolaryngology, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
- Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Min Huang
- Department of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Fuzhou, 350000, China
- Department of Otorhinolaryngology, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
- Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Xiu-Ling Fang
- Department of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Fuzhou, 350000, China
- Department of Otorhinolaryngology, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China
- Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China
| | - Guo-Hao Chen
- Department of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Fuzhou, 350000, China.
- Department of Otorhinolaryngology, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China.
- Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
| | - Sheng-Nan Ye
- Department of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Chazhong Road 20th, Fuzhou, 350000, China.
- Department of Otorhinolaryngology, Binhai Campus of the First Affiliated Hospital, National Regional Medical Center, Fujian Medical University, Fuzhou, 350212, China.
- Fujian Institute of Otorhinolaryngology, The First Affiliated Hospital, Fujian Medical University, Fuzhou, 350005, China.
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Chen Y, Yang R, Qi B, Shan Z. Peptidoglycan-Chi3l1 interaction shapes gut microbiota in intestinal mucus layer. eLife 2024; 13:RP92994. [PMID: 39373714 PMCID: PMC11458176 DOI: 10.7554/elife.92994] [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] [Indexed: 10/08/2024] Open
Abstract
The balanced gut microbiota in intestinal mucus layer plays an instrumental role in the health of the host. However, the mechanisms by which the host regulates microbial communities in the mucus layer remain largely unknown. Here, we discovered that the host regulates bacterial colonization in the gut mucus layer by producing a protein called Chitinase 3-like protein 1 (Chi3l1). Intestinal epithelial cells are stimulated by the gut microbiota to express Chi3l1. Once expressed, Chi3l1 is secreted into the mucus layer where it interacts with the gut microbiota, specifically through a component of bacterial cell walls called peptidoglycan. This interaction between Chi3l1 and bacteria is beneficial for the colonization of bacteria in the mucus, particularly for Gram-positive bacteria like Lactobacillus. Moreover, a deficiency of Chi3l1 leads to an imbalance in the gut microbiota, which exacerbates colitis induced by dextran sodium sulfate. By performing fecal microbiota transplantation from Villin-cre mice or replenishing Lactobacillus in IEC∆Chil1 mice, we were able to restore their colitis to the same level as that of Villin-cre mice. In summary, this study shows a 'scaffold model' for microbiota homeostasis by interaction between intestinal Chi3l1 and bacteria cell wall interaction, and it also highlights that an unbalanced gut microbiota in the intestinal mucus contributes to the development of colitis.
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Affiliation(s)
- Yan Chen
- Southwest United Graduate School, Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan UniversityKunmingChina
| | - Ruizhi Yang
- Southwest United Graduate School, Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan UniversityKunmingChina
| | - Bin Qi
- Southwest United Graduate School, Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan UniversityKunmingChina
| | - Zhao Shan
- Southwest United Graduate School, Yunnan Key Laboratory of Cell Metabolism and Diseases, State Key Laboratory of Conservation and Utilization of Bio-resources in Yunnan, Center for Life Sciences, School of Life Sciences, Yunnan UniversityKunmingChina
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7
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Olson MA, Cullimore C, Hutchison WD, Grimsrud A, Nobrega D, De Buck J, Barkema HW, Wilson E, Pickett BE, Erickson DL. Genes associated with fitness and disease severity in the pan-genome of mastitis-associated Escherichia coli. Front Microbiol 2024; 15:1452007. [PMID: 39268542 PMCID: PMC11390585 DOI: 10.3389/fmicb.2024.1452007] [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: 06/20/2024] [Accepted: 08/19/2024] [Indexed: 09/15/2024] Open
Abstract
Introduction Bovine mastitis caused by Escherichia coli compromises animal health and inflicts substantial product losses in dairy farming. It may manifest as subclinical through severe acute disease and can be transient or persistent in nature. Little is known about bacterial factors that impact clinical outcomes or allow some strains to outcompete others in the mammary gland (MG) environment. Mastitis-associated E. coli (MAEC) may have distinctive characteristics which may contribute to the varied nature of the disease. Given their high levels of intraspecies genetic variability, virulence factors of commonly used MAEC model strains may not be relevant to all members of this group. Methods In this study, we sequenced the genomes of 96 MAEC strains isolated from cattle with clinical mastitis (CM). We utilized clinical severity data to perform genome-wide association studies to identify accessory genes associated with strains isolated from mild or severe CM, or with high or low competitive fitness during in vivo competition assays. Genes associated with mastitis pathogens or commensal strains isolated from bovine sources were also identified. Results A type-2 secretion system (T2SS) and a chitinase (ChiA) exported by this system were strongly associated with pathogenic isolates compared with commensal strains. Deletion of chiA from MAEC isolates decreased their adherence to cultured bovine mammary epithelial cells. Discussion The increased fitness associated with strains possessing this gene may be due to better attachment in the MG. Overall, these results provide a much richer understanding of MAEC and suggest bacterial processes that may underlie the clinical diversity associated with mastitis and their adaptation to this unique environment.
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Affiliation(s)
- Michael A Olson
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - Caz Cullimore
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - Weston D Hutchison
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - Aleksander Grimsrud
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - Diego Nobrega
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Jeroen De Buck
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Herman W Barkema
- Faculty of Veterinary Medicine, University of Calgary, Calgary, AB, Canada
| | - Eric Wilson
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - Brett E Pickett
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
| | - David L Erickson
- Department of Microbiology and Molecular Biology, Brigham Young University, Provo, UT, United States
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Fan Y, Meng Y, Hu X, Liu J, Qin X. Uncovering novel mechanisms of chitinase-3-like protein 1 in driving inflammation-associated cancers. Cancer Cell Int 2024; 24:268. [PMID: 39068486 PMCID: PMC11282867 DOI: 10.1186/s12935-024-03425-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2024] [Accepted: 07/01/2024] [Indexed: 07/30/2024] Open
Abstract
Chitinase-3-like protein 1 (CHI3L1) is a secreted glycoprotein that is induced and regulated by multiple factors during inflammation in enteritis, pneumonia, asthma, arthritis, and other diseases. It is associated with the deterioration of the inflammatory environment in tissues with chronic inflammation caused by microbial infection or autoimmune diseases. The expression of CHI3L1 expression is upregulated in several malignant tumors, underscoring the crucial role of chronic inflammation in the initiation and progression of cancer. While the precise mechanism connecting inflammation and cancer is unclear, the involvement of CHI3L1 is involved in chronic inflammation, suggesting its role as a contributing factor to in the link between inflammation and cancer. CHI3L1 can aggravate DNA oxidative damage, induce the cancerous phenotype, promote the development of a tumor inflammatory environment and angiogenesis, inhibit immune cells, and promote cancer cell growth, invasion, and migration. Furthermore, it participates in the initiation of cancer progression and metastasis by binding with transmembrane receptors to mediate intracellular signal transduction. Based on the current research on CHI3L1, we explore introduce the receptors that interact with CHI3L1 along with the signaling pathways that may be triggered during chronic inflammation to enhance tumorigenesis and progression. In the last section of the article, we provide a brief overview of anti-inflammatory therapies that target CHI3L1.
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Affiliation(s)
- Yan Fan
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Yuan Meng
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Xingwei Hu
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Jianhua Liu
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China
| | - Xiaosong Qin
- Department of Laboratory Medicine, Liaoning Clinical Research Center for Laboratory Medicine, Shengjing Hospital of China Medical University, Shenyang, Liaoning, 110122, China.
- Liaoning Clinical Research Center for Laboratory Medicine, Shenyang, Liaoning Province, China.
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Qin Y, Zhao W, Li Q, Cai Z, Wang G, Wang N, Ma L. Inhibition of Chitinase-3-like Protein 1 Reduced Epithelial-Mesenchymal Transition and Vascular Epithelial Cadherin Expression in Oesophageal Squamous Cell Carcinoma. IRANIAN JOURNAL OF BIOTECHNOLOGY 2024; 22:e3693. [PMID: 39737205 PMCID: PMC11682521 DOI: 10.30498/ijb.2024.394737.3693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Accepted: 09/16/2024] [Indexed: 01/01/2025]
Abstract
Background Oesophageal cancer (EC) is one of the common malignant tumors, and the prognosis of patients is poor. Further exploration of EC pathogenesis remains warranted. Objective The relationship between vascular epithelial cadherin (VE-cadherin) and chitinase-3-like protein 1 (CHI3L1) in EC is currently unknown. To further explore the relationship, immunohistochemical staining was performed to detect the expression level of CHI3L1 and VE-cadherin in oesophageal squamous cell carcinoma ( ESCC). Materials and Methods Small interfering RNAs (siRNAs) inhibited CHI3L1 expression in KYSE-150 and TE1 cells. Western blot and quantitative fluorescence polymerase chain reaction were used to detect the levels of CHI3L1, VE-cadherin and epithelial-mesenchymal transition (EMT)-related proteins in vitro and in vivo, and KYSE-150 cells were used to establish an in-vivo model and observe tumour growth. Results High levels of CHI3L1 and VE-cadherin expression were closely associated with the progression of ESCC; the pathologic tumour-node-metastasis stage was also closely related with the progression of ESCC (p < 0.05). High levels of CHI3L1 and VE-cadherin expression led to poor prognosis in patients with EC. In KYSE-150 and TE1 EC cell lines, the invasion, migration and proliferation of cells decreased, and the apoptotic rate increased after CHI3L1 expression was decreased using siRNA. The CHI3L1, VE-cadherin, Snail, Twist1 protein and mRNA expression levels decreased, whereas the E-cadherin levels increased. Conclusions Chitinase-3-like protein 1 could promote the EMT of ESCC, and the inhibition of CHI3L1 decreases the expression of VE-cadherin, which inhibits tumour angiogenesis and tumour progression in ESCC.
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Affiliation(s)
- Yanzi Qin
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - Wenjun Zhao
- Department of Emergency Internal Medicine, The Third the People′s Hospital of Bengbu, Bengbu 233000, China
| | - Qicai Li
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Bengbu Medical University,Bengbu 233000, China
| | - Zhaogeng Cai
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
| | - Guowen Wang
- Department of Thoracic and Cardiovascular Surgery, The First Affiliated Hospital of Bengbu Medical University,Bengbu 233000, China
| | - Nan Wang
- Department of Critical Care Medicine, The Fourth Affiliated Hospital of Anhui Medical University, Hefei 230601, China
| | - Li Ma
- Department of Pathology, The First Affiliated Hospital of Bengbu Medical University, Bengbu 233000, China
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10
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Mizoguchi E. Brown-Kurume Exchange Programs Have Developed Through Many Unexpected Encounters and Relationships. Kurume Med J 2024; 69:119-126. [PMID: 38233182 DOI: 10.2739/kurumemedj.ms6934007] [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] [Indexed: 01/19/2024]
Abstract
In July 1992, my 24 years of studying abroad in the US as a researcher at Harvard Medical School started. During this period, I met many outstanding scholars who conducted some of the world's leading research projects. In particular, the opportunity to collaborate with Dr. Jack A. Elias, Professor and Dean Emeritus of the Faculty of Medicine at Brown University, on a project focusing on a molecule called Chitinase 3-like 1 was very helpful to my career, and eventually led to my current position as Professor in charge of international medical exchange at Kurume University School of Medicine. By strengthening the foundation of our exchange programs and actively promoting international joint research projects, I would like to raise the global name recognition of Kurume University.
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Affiliation(s)
- Emiko Mizoguchi
- Department of Immunology, Kurume University School of Medicine
- Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School
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Mizoguchi E, Sadanaga T, Nanni L, Wang S, Mizoguchi A. Recently Updated Role of Chitinase 3-like 1 on Various Cell Types as a Major Influencer of Chronic Inflammation. Cells 2024; 13:678. [PMID: 38667293 PMCID: PMC11049018 DOI: 10.3390/cells13080678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
Chitinase 3-like 1 (also known as CHI3L1 or YKL-40) is a mammalian chitinase that has no enzymatic activity, but has the ability to bind to chitin, the polymer of N-acetylglucosamine (GlcNAc). Chitin is a component of fungi, crustaceans, arthropods including insects and mites, and parasites, but it is completely absent from mammals, including humans and mice. In general, chitin-containing organisms produce mammalian chitinases, such as CHI3L1, to protect the body from exogenous pathogens as well as hostile environments, and it was thought that it had a similar effect in mammals. However, recent studies have revealed that CHI3L1 plays a pathophysiological role by inducing anti-apoptotic activity in epithelial cells and macrophages. Under chronic inflammatory conditions such as inflammatory bowel disease and chronic obstructive pulmonary disease, many groups already confirmed that the expression of CHI3L1 is significantly induced on the apical side of epithelial cells, and activates many downstream pathways involved in inflammation and carcinogenesis. In this review article, we summarize the expression of CHI3L1 under chronic inflammatory conditions in various disorders and discuss the potential roles of CHI3L1 in those disorders on various cell types.
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Affiliation(s)
- Emiko Mizoguchi
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
- Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School, Providence, RI 02912, USA
| | - Takayuki Sadanaga
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
- Department of Molecular Microbiology and Immunology, Brown University Alpert Medical School, Providence, RI 02912, USA
| | - Linda Nanni
- Catholic University of the Sacred Heart, 00168 Rome, Italy;
| | - Siyuan Wang
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
| | - Atsushi Mizoguchi
- Department of Immunology, Kurume University School of Medicine, Kurume 830-0011, Japan; (T.S.); (S.W.); (A.M.)
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Černelič Bizjak M, Jenko Pražnikar Z, Kenig S, Hladnik M, Bandelj D, Gregori A, Kranjc K. Effect of erinacine A-enriched Hericium erinaceus supplementation on cognition: A randomized, double-blind, placebo-controlled pilot study. J Funct Foods 2024; 115:106120. [DOI: 10.1016/j.jff.2024.106120] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2025] Open
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Blazevic N, Rogic D, Pelajic S, Miler M, Glavcic G, Ratkajec V, Vrkljan N, Bakula D, Hrabar D, Pavic T. YKL-40 as a biomarker in various inflammatory diseases: A review. Biochem Med (Zagreb) 2024; 34:010502. [PMID: 38125621 PMCID: PMC10731731 DOI: 10.11613/bm.2024.010502] [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: 02/22/2023] [Accepted: 09/04/2023] [Indexed: 12/23/2023] Open
Abstract
YKL-40 or Chitinase-3-Like Protein 1 (CHI3L1) is a highly conserved glycoprotein that binds heparin and chitin in a non-enzymatic manner. It is a member of the chitinase protein family 18, subfamily A, and unlike true chitinases, YKL-40 is a chitinase-like protein without enzymatic activity for chitin. Although its accurate function is yet unknown, the pattern of its expression in the normal and disease states suggests its possible engagement in apoptosis, inflammation and remodeling or degradation of the extracellular matrix. During an inflammatory response, YKL-40 is involved in a complicated interaction between host and bacteria, both promoting and attenuating immune response and potentially being served as an autoantigen in a vicious circle of autoimmunity. Based on its pathophysiology and mechanism of action, the aim of this review was to summarize research on the growing role of YKL-40 as a persuasive biomarker for inflammatory diseases' early diagnosis, prediction and follow-up (e.g., cardiovascular, gastrointestinal, endocrinological, immunological, musculoskeletal, neurological, respiratory, urinary, infectious) with detailed structural and functional background of YKL-40.
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Affiliation(s)
- Nina Blazevic
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Dunja Rogic
- Department of Laboratory Diagnostics, University Hospital Center Zagreb, Zagreb, Croatia
| | - Stipe Pelajic
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Marijana Miler
- Department of Clinical Chemistry, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Goran Glavcic
- Department of Surgery, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Valentina Ratkajec
- Department of Gastroenterology, General Hospital Virovitica, Virovitica, Croatia
| | - Nikolina Vrkljan
- Department of Internal Medicine, Intensive Care Unit, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Dejan Bakula
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Davor Hrabar
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
| | - Tajana Pavic
- Department of Gastroenterology and Hepatology, Sestre milosrdnice University Hospital Center, Zagreb, Croatia
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Wu GL, Li L, Chen XY, Zhang WF, Wu JB, Yu X, Chen HJ. Machine learning-based B cell-related diagnostic biomarker signature and molecular subtypes characteristic of ulcerative colitis. Aging (Albany NY) 2024; 16:2774-2788. [PMID: 38319729 PMCID: PMC10911385 DOI: 10.18632/aging.205510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Accepted: 01/03/2024] [Indexed: 02/08/2024]
Abstract
As an inflammatory bowel disease, ulcerative colitis (UC) does not respond well to current treatments. It is of positive clinical significance to further study the pathogenesis of UC and find new therapeutic targets. B lymphocytes play an important role in the pathogenesis of UC. The effect of anti-CD20 therapy on UC also provides new evidence for the involvement of B cells in UC process additionally, suggesting the important role and potential therapeutic value of B cells in UC. In this study, we screened the most critical immune cell-related gene modules associated with UC and found that activated B cells were closely related to the gene modules. Subsequently, key activated B cell-associated gene (BRG) signatures were obtained based on WGCNA and differential expression analysis, and three overlapping BRG-associated genes were obtained by RF and LASSO algorithms as BRG-related diagnostic biomarkers for UC. Nomogram model was further performed to evaluate the diagnostic ability of BRG-related diagnostic biomarkers, subsequently followed by UC molecular subsets identification and immunoinfiltration analysis. We also further verified the expressions of the three screened BRGs in vitro by using an LPS-induced NCM460 cell line model. Our results provide new evidence and potential intervention targets for the role of B cells in UC from a new perspective.
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Affiliation(s)
- Guo-Liang Wu
- First Clinical Medical College, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, China
- Department of Anorectal Section, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
| | - Li Li
- Department of Endocrinology, The Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, Shandong 250014, China
| | - Xiao-Yao Chen
- Department of Anorectal Section, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong 250014, China
| | - Wei-Feng Zhang
- Department of Colorectal Surgery, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, China
- Department of Anorectal Section, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
| | - Jun-Bo Wu
- Department of Colorectal Surgery, Hengyang Central Hospital, Hengyang, Hunan 421001, China
| | - Xiaoning Yu
- Department of Geriatrics, Hematology and Oncology Unit, Qilu Hospital of Shandong University, Jinan, China
| | - Hong-Jin Chen
- Department of Anorectal Section, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221000, China
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Fargeas M, Faure F, Douadi C, Chevarin C, Birer A, Sivignon A, Rodrigues M, Denizot J, Billard E, Barnich N, Buisson A. ChiA: a major player in the virulence of Crohn's disease-associated adherent and invasive Escherichia coli (AIEC). Gut Microbes 2024; 16:2412667. [PMID: 39397494 PMCID: PMC11486038 DOI: 10.1080/19490976.2024.2412667] [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: 07/17/2024] [Revised: 09/09/2024] [Accepted: 09/30/2024] [Indexed: 10/15/2024] Open
Abstract
We investigated the role of ChiA and its associated polymorphisms in the interaction between Crohn's disease (CD)-associated adherent-invasive Escherichia coli (AIEC) and intestinal mucosa. We observed a higher abundance of chiA among the metagenome of CD patients compared to healthy subjects. In dextran sulfate sodium-induced colitis mice model, AIEC-LF82∆chiA colonization was reduced in ileal, colonic and fecal samples compared to wild-type LF82. The binding of ChiA to recombinant human CHI3L1 or mucus was higher with the pathogenic polymorphism. The strength of ChiA-mucin interaction was 300-fold stronger than ChiA-rhCHI3L1. ChiA was able to degrade mucin to promote its growth and enabled LF82 to get closer to epithelial cells. The pathogenic polymorphism of ChiA had a stronger impact on mucus degradation than on the binding capability of AIEC to adhere to the intestinal epithelium. We observed that ChiA could favor an efficient bacterial invasion of intestinal crypts, and that ChiA, especially its pathogenic polymorphism, gives LF82 an advantage to uptake within Peyer's patches, macrophages and mesenteric lymph nodes. All together, these data support the role of ChiA in the virulence of AIEC and show that it could be a promising target to reduce AIEC colonization in patients with CD.
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Affiliation(s)
- Margot Fargeas
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Frederic Faure
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
- 3iHP, CHU Clermont-Ferrand, Service d’Hépato-Gastro Entérologie, Université Clermont Auvergne, Inserm, Clermont-Ferrand, France
| | - Clara Douadi
- Centre de Recherche Saint-Antoine, Sorbonne Université, Inserm, Paris, France
- Paris Center for Microbiome Medicine (PaCeMM) FHU, AP-HP, Paris, France
| | - Caroline Chevarin
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Aurélien Birer
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Adeline Sivignon
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Michael Rodrigues
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Jérémy Denizot
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Elisabeth Billard
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Nicolas Barnich
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
| | - Anthony Buisson
- Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), Université Clermont Auvergne/Inserm, Clermont-Ferrand, France
- 3iHP, CHU Clermont-Ferrand, Service d’Hépato-Gastro Entérologie, Université Clermont Auvergne, Inserm, Clermont-Ferrand, France
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Sipeki N, Kovats PJ, Deutschmann C, Schierack P, Roggenbuck D, Papp M. Location-based prediction model for Crohn's disease regarding a novel serological marker, anti-chitinase 3-like 1 autoantibodies. World J Gastroenterol 2023; 29:5728-5750. [PMID: 38075846 PMCID: PMC10701337 DOI: 10.3748/wjg.v29.i42.5728] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/28/2023] [Revised: 10/03/2023] [Accepted: 11/02/2023] [Indexed: 11/13/2023] Open
Abstract
BACKGROUND Defective neutrophil regulation in inflammatory bowel disease (IBD) is thought to play an important role in the onset or manifestation of IBD, as it could lead to damage of the intestinal mucosal barrier by the infiltration of neutrophils in the inflamed mucosa and the accumulation of pathogens. Like neutrophils in the context of innate immune responses, immunoglobulin A (IgA) as an acquired immune response partakes in the defense of the intestinal epithelium. Under normal conditions, IgA contributes to the elimination of microbes, but in connection with the loss of tolerance to chitinase 3-like 1 (CHI3L1) in IBD, IgA could participate in CHI3L1-mediated improved adhesion and invasion of potentially pathogenic microorganisms. The tolerance brake to CHI3L1 and the occurrence of IgA autoantibodies to this particular target, the exact role and underlying mechanisms of CHI3L1 in the pathogenesis of IBD are still unclear. AIM To determine the predictive potential of Ig subtypes of a novel serological marker, anti-CHI3L1 autoantibodies (aCHI3L1) in determining the disease phenotype, therapeutic strategy and long-term disease course in a prospective referral cohort of adult IBD patients. METHODS Sera of 257 Crohn's disease (CD) and 180 ulcerative colitis (UC) patients from a tertiary IBD referral center of Hungary (Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen) were assayed for IgG, IgA, and secretory IgA (sIgA) type aCHI3L1 by enzyme-linked immunosorbent assay using recombinant CHI3L1, along with 86 healthy controls (HCONT). RESULTS The IgA type was more prevalent in CD than in UC (29.2% vs 11.1%) or HCONT (2.83%; P < 0.0001 for both). However, sIgA subtype aCHI3L1 positivity was higher in both CD and UC patients than in HCONT (39.3% and 32.8% vs 4.65%, respectively; P < 0.0001). The presence of both IgA and sIgA aCHI3L1 antibodies was associated with colonic involvement (P < 0.0001 and P = 0.038, respectively) in patients with CD. Complicated disease behavior at sample procurement was associated with aCHI3L1 sIgA positivity (57.1% vs 36.0%, P = 0.009). IgA type aCH3L1 was more prevalent in patients with frequent relapse during the disease course in the CD group (46.9% vs 25.7%, P = 0.005). In a group of patients with concomitant presence of pure inflammatory luminal disease and colon involvement at the time of diagnosis, positivity for IgA or sIgA type aCH3L1 predicted faster progression towards a complicated disease course in time-dependent models. This association disappeared after merging subgroups of different disease locations. CONCLUSION CHI3L1 is a novel neutrophil autoantigenic target in IBD. The consideration of antibody classes along with location-based prediction may transform the future of serology in IBD.
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Affiliation(s)
- Nora Sipeki
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
| | - Patricia Julianna Kovats
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
- Kálmán Laki Doctoral School, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
| | - Claudia Deutschmann
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
- Faculty of Health Sciences Brandenburg, Brandenburg University of Technology Cottbus-Senftenberg, Senftenberg 01968, Germany
- Medipan GmbH & GA Generic Assays GmbH, Dahlewitz-Berlin 15827, Germany
| | - Maria Papp
- Division of Gastroenterology, Department of Internal Medicine, Faculty of Medicine, University of Debrecen, Debrecen H-4032, Hungary
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Zhao H, Huang M, Jiang L. Potential Roles and Future Perspectives of Chitinase 3-like 1 in Macrophage Polarization and the Development of Diseases. Int J Mol Sci 2023; 24:16149. [PMID: 38003338 PMCID: PMC10671302 DOI: 10.3390/ijms242216149] [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: 10/16/2023] [Revised: 11/03/2023] [Accepted: 11/05/2023] [Indexed: 11/26/2023] Open
Abstract
Chitinase-3-like protein 1 (CHI3L1), a chitinase-like protein family member, is a secreted glycoprotein that mediates macrophage polarization, inflammation, apoptosis, angiogenesis, and carcinogenesis. Abnormal CHI3L1 expression has been associated with multiple metabolic and neurological disorders, including diabetes, atherosclerosis, and Alzheimer's disease. Aberrant CHI3L1 expression is also reportedly associated with tumor migration and metastasis, as well as contributions to immune escape, playing important roles in tumor progression. However, the physiological and pathophysiological roles of CHI3L1 in the development of metabolic and neurodegenerative diseases and cancer remain unclear. Understanding the polarization relationship between CHI3L1 and macrophages is crucial for disease progression. Recent research has uncovered the complex mechanisms of CHI3L1 in different diseases, highlighting its close association with macrophage functional polarization. In this article, we review recent findings regarding the various disease types and summarize the relationship between macrophages and CHI3L1. Furthermore, this article also provides a brief overview of the various mechanisms and inhibitors employed to inhibit CHI3L1 and disrupt its interaction with receptors. These endeavors highlight the pivotal roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of metabolic diseases, neurodegenerative diseases, and cancers.
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Affiliation(s)
| | - Mingdong Huang
- College of Chemistry, Fuzhou University, Fuzhou 350116, China;
| | - Longguang Jiang
- College of Chemistry, Fuzhou University, Fuzhou 350116, China;
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Teratani Y. Chitinase 3-Like-1 Expression Is Upregulated Under Inflammatory Conditions in Human Oral Epithelial Cells. Kurume Med J 2023; 68:221-228. [PMID: 37380444 DOI: 10.2739/kurumemedj.ms6834014] [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] [Indexed: 06/30/2023]
Abstract
OBJECTIVE Chitinase 3-like-1 (CHI3L1), also known as YKL-40, is a partially secreted glycoprotein and is involved in inflammatory disorders, including inflammatory bowel diseases. CHI3L1 is known to play a role in biological responses such as cell proliferation, tissue remodeling, and inflammation. CHI3L1 forms an immune complex (known as a Chitosome complex) with IL-13 receptor alpha 2 (IL-13 Rα2) and transmembrane protein 219 (TMEM219) to activate the MAPK/ERK and PKB/AKT signaling pathways. The objective of this study is to investigate how the expressions of CHI3L1 and a Chitosome complex in human oral cavity epithelial cells are linked with intraoral inflammatory diseases. METHOD CHI3L1 and Chitosome complex mRNA expressions were analyzed using human oral squamous cancer cell lines, HSC3 and HSC4 cells. Signaling activation in HSC4 cells was analyzed by using the western blot technique. Immunohistological analysis was performed using surgical samples obtained from patients with benign oral cavity tumors and cysts. RESULTS Increased expression of CHI3L1 was observed in both HSC3 and HSC4 cells after TNFα stimulation. The expression of Chitosome complex factors increased as CHI3L1 levels increased, resulting in the activation of a downstream signaling pathway. Among the intraoral tissues, the epithelial cells from inflammatory lesions, but not benign tumors, were found to be intensively stained with the anti-CHI3L1 antibody. CONCLUSION It was indicated that the formation of a Chitosome complex is induced during inflammation, leading to the activation of signaling pathways.
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Affiliation(s)
- Yui Teratani
- Department of Immunology, Kurume University School of Medicine
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Bonet-Rossinyol Q, Camprubí-Font C, López-Siles M, Martinez-Medina M. Identification of differences in gene expression implicated in the Adherent-Invasive Escherichia coli phenotype during in vitro infection of intestinal epithelial cells. Front Cell Infect Microbiol 2023; 13:1228159. [PMID: 37767199 PMCID: PMC10519790 DOI: 10.3389/fcimb.2023.1228159] [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: 05/24/2023] [Accepted: 07/21/2023] [Indexed: 09/29/2023] Open
Abstract
Introduction Adherent-invasive Escherichia coli (AIEC) is strongly associated with the pathogenesis of Crohn's disease (CD). However, no molecular markers currently exist for AIEC identification. This study aimed to identify differentially expressed genes (DEGs) between AIEC and non-AIEC strains that may contribute to AIEC pathogenicity and to evaluate their utility as molecular markers. Methods Comparative transcriptomics was performed on two closely related AIEC/non-AIEC strain pairs during Intestine-407 cell infection. DEGs were quantified by RT-qPCR in the same RNA extracts, as well as in 14 AIEC and 23 non-AIEC strains to validate the results across a diverse strain collection. Binary logistical regression was performed to identify DEGs whose quantification could be used as AIEC biomarkers. Results Comparative transcriptomics revealed 67 differences in expression between the two phenotypes in the strain pairs, 50 of which (81.97%) were corroborated by RT-qPCR. When explored in the whole strain collection, 29 DEGs were differentially expressed between AIEC and non-AIEC phenotypes (p-value < 0.042), and 42 genes between the supernatant fraction of infected cell cultures and the cellular fraction containing adhered and intracellular bacteria (p-value < 0.049). Notably, six DEGs detected in the strain collection were implicated in arginine biosynthesis and five in colanic acid synthesis. Furthermore, two biomarkers based on wzb and cueR gene expression were proposed with an accuracy of ≥ 85% in our strain collection. Discussion This is the first transcriptomic study conducted using AIEC-infected cell cultures. We have identified several genes that may be involved in AIEC pathogenicity, two of which are putative biomarkers for identification.
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Khandelwal P, Lounder DT, Bartlett A, Haberman Y, Jegga AG, Ghandikota S, Koo J, Luebbering N, Leino D, Abdullah S, Loveless M, Minar P, Lake K, Litts B, Karns R, Nelson AS, Denson LA, Davies SM. Transcriptome analysis in acute gastrointestinal graft- versus host disease reveals a unique signature in children and shared biology with pediatric inflammatory bowel disease. Haematologica 2023; 108:1803-1816. [PMID: 36727399 PMCID: PMC10316272 DOI: 10.3324/haematol.2022.282035] [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: 10/10/2022] [Accepted: 01/25/2023] [Indexed: 02/03/2023] Open
Abstract
We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion. Mitochondrial genes were among the top downregulated genes. Immune deconvolution identified a macrophage cellular signature. Weighted gene co-expression network analysis showed enrichment of genes in the ERK1/2 cascade. Transcriptome data from 206 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GvHD and UC. Comparison with the UC transcriptome showed both shared and distinct pathways. Both UC and GvHD transcriptomes shared an innate antimicrobial signature and FCγ1RA/CD64 was upregulated in both acute GvHD (log-fold increase 1.7, P=0.001) and UC. Upregulation of the ERK1/2 cascade pathway was specific to GvHD. We performed additional experiments to confirm transcriptomics. Firstly, we examined phosphorylation of ERK (pERK) by immunohistochemistry on GI biopsies (acute GvHD n=10, no GvHD n=10). pERK staining was increased in acute GvHD biopsies compared to biopsies without acute GvHD (P=0.001). Secondly, plasma CD64, measured by enzyme-linked immunsorbant assay (n=85) was elevated in acute GI GvHD (P<0.001) compared with those without and was elevated in GVHD compared with inflammatory bowel disease (n=47) (P<0.001), confirming the upregulated expression seen in the transcriptome.
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Affiliation(s)
- Pooja Khandelwal
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229.
| | - Dana T Lounder
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Allison Bartlett
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Yael Haberman
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Sheba Medical Center, Hashomer, affiliated with the Aviv University, Israel 52620
| | - Anil G Jegga
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Sudhir Ghandikota
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Biomedical Informatics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Jane Koo
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Nathan Luebbering
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Daniel Leino
- Department of Pathology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Sheyar Abdullah
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Michaela Loveless
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Phillip Minar
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Kelly Lake
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Bridget Litts
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Rebekah Karns
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Adam S Nelson
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
| | - Lee A Denson
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229; Division of Gastroenterology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229
| | - Stella M Davies
- Division of Bone Marrow Transplant and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229; Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati OH 45229
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21
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MicroRNA Profiles in Intestinal Epithelial Cells in a Mouse Model of Sepsis. Cells 2023; 12:cells12050726. [PMID: 36899862 PMCID: PMC10001189 DOI: 10.3390/cells12050726] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Revised: 02/22/2023] [Accepted: 02/22/2023] [Indexed: 03/03/2023] Open
Abstract
Sepsis is a systemic inflammatory disorder that leads to the dysfunction of multiple organs. In the intestine, the deregulation of the epithelial barrier contributes to the development of sepsis by triggering continuous exposure to harmful factors. However, sepsis-induced epigenetic changes in gene-regulation networks within intestinal epithelial cells (IECs) remain unexplored. In this study, we analyzed the expression profile of microRNAs (miRNAs) in IECs isolated from a mouse model of sepsis generated via cecal slurry injection. Among 239 miRNAs, 14 miRNAs were upregulated, and 9 miRNAs were downregulated in the IECs by sepsis. Upregulated miRNAs in IECs from septic mice, particularly miR-149-5p, miR-466q, miR-495, and miR-511-3p, were seen to exhibit complex and global effects on gene regulation networks. Interestingly, miR-511-3p has emerged as a diagnostic marker in this sepsis model due to its increase in blood in addition to IECs. As expected, mRNAs in the IECs were remarkably altered by sepsis; specifically, 2248 mRNAs were decreased, while 612 mRNAs were increased. This quantitative bias may be possibly derived, at least partly, from the direct effects of the sepsis-increased miRNAs on the comprehensive expression of mRNAs. Thus, current in silico data indicate that there are dynamic regulatory responses of miRNAs to sepsis in IECs. In addition, the miRNAs that were increased with sepsis had enriched downstream pathways including Wnt signaling, which is associated with wound healing, and FGF/FGFR signaling, which has been linked to chronic inflammation and fibrosis. These modifications in miRNA networks in IECs may lead to both pro- and anti-inflammatory effects in sepsis. The four miRNAs discovered above were shown to putatively target LOX, PTCH1, COL22A1, FOXO1, or HMGA2, via in silico analysis, which were associated with Wnt or inflammatory pathways and selected for further study. The expressions of these target genes were downregulated in sepsis IECs, possibly through posttranscriptional modifications of these miRNAs. Taken together, our study suggests that IECs display a distinctive miRNA profile which is capable of comprehensively and functionally reshaping the IEC-specific mRNA landscape in a sepsis model.
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22
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Zhang Y, Li Y, Li F, Li L, Wang C, Wang H, Chen Y, Zhang C, Zhang Y, Wang W. Differential expression of Chitinase 3-Like 1 protein in appendicitis and appendix carcinomas. J Clin Lab Anal 2022; 36:e24790. [PMID: 36447423 PMCID: PMC9756995 DOI: 10.1002/jcla.24790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 10/19/2022] [Accepted: 11/13/2022] [Indexed: 12/03/2022] Open
Abstract
BACKGROUND Chitinase 3-Like 1 (CHI3L1) has been used as an inflammatory biomarker for a variety of diseases, but its expression in acute appendicitis and appendix carcinomas remains unclear. METHODS Sixty cases of patients were studied, including 46 acute appendicitis and 14 appendix carcinomas. We divided the acute appendicitis group into acute uncomplicated appendicitis (AUA), suppurative appendicitis (SA), and gangrenous appendicitis (GA). The appendix carcinoma group was divided into appendiceal neuroendocrine neoplasms (ANENs) and appendiceal mucinous neoplasms (AMN). Controls were 32 healthy donors. Blood neutrophil to lymphocyte ratio (NLR), CHI3L1, C-reactive protein (CRP), interleukin-6 (IL-6), and serum amyloid A (SAA) were measured in the patients. Meanwhile, immunohistochemistry and immunofluorescence were used to identify the expression level and location of CHI3L1 in different cell types in appendix tissues. RESULTS Compared with the controls, CHI3L1 serum levels were up-regulated in SA, GA, and AMN groups, while no significant difference was observed in the AUA and ANEN groups. Immunofluorescence revealed that CHI3L1 expression was high in macrophages and adenocarcinoma cells of appendix tissues but not in the neuroendocrine carcinoma tissues. Moreover, levels of NLR and CRP in the SA and GA groups were considerably higher than in the control group. IL-6 and SAA in SA, GA, ANENs, and AMN groups were also increased compared with the control group. In addition, CHI3L1 displayed good performance in predicting appendicitis, with an AUC of 0.862. CONCLUSION CHI3L1 was highly expressed in acute appendicitis and appendiceal mucinous neoplasms, which can be used as a novel biomarker predicting appendicitis.
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Affiliation(s)
- Yong Zhang
- Department of General SurgeryThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Yanping Li
- Anesthesiology DepartmentThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Fei Li
- Center for Clinical LaboratoryThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Lingxing Li
- Department of Cardiovascular MedicineThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Chaoqun Wang
- Center for Clinical LaboratoryThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Han Wang
- Medical Image CenterThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Yun Chen
- Department of Minimally invasive oncologyThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Chunling Zhang
- Department of GynecologyThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Yi Zhang
- Department of Rehabilitation MedicineThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
| | - Wenyang Wang
- Center for Clinical LaboratoryThe Affiliated Taian City Central Hospital of Qingdao UniversityTaianChina
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23
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Douadi C, Vazeille E, Chambon C, Hébraud M, Fargeas M, Dodel M, Coban D, Pereira B, Birer A, Sauvanet P, Buisson A, Barnich N. Anti-TNF Agents Restrict Adherent-invasive Escherichia coli Replication Within Macrophages Through Modulation of Chitinase 3-like 1 in Patients with Crohn's Disease. J Crohns Colitis 2022; 16:1140-1150. [PMID: 35022663 DOI: 10.1093/ecco-jcc/jjab236] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2021] [Revised: 12/01/2021] [Accepted: 01/11/2022] [Indexed: 12/13/2022]
Abstract
BACKGROUND AND AIMS The mechanism of action of anti-tumour necrosis factor [anti-TNF] agents could implicate macrophage modulation in Crohn's disease [CD]. As CD macrophages are defective in controlling CD-associated adherent-invasive Escherichia coli [AIEC], anti-TNF agents could limit AIEC replication within macrophages. We assessed the effect of anti-TNF agents on AIEC survival within monocyte-derived macrophages [MDMs] from CD patients and attempted to identify the proteins involved. METHODS Peripheral blood MDMs were obtained from 44 CD patients [22 with and 22 without anti-TNF agents]. MDMs were infected with reference strain AIEC-LF82. Proteomic analysis was performed before and 6 h after AIEC-LF82 infection. RESULTS AIEC-LF82 survival was lower in MDMs from CD patients receiving anti-TNF agents compared to those who did not [-73%, p = 0.006]. After AIEC-LF82 infection, the levels of CD82 [p = 0.007], ILF3 [Interleukin enhancer-binding factor 3; p = 0.001], FLOT-1 [Flotillin-1; p = 0.007] and CHI3L1 [Chitinase 3-like 1; p = 0.035] proteins were different within CD-MDMs depending on anti-TNF exposure. FLOT-1 [ϱ = -0.44; p = 0.038] and CHI3L1 [ϱ = 0.57, p = 0.006] levels were inversely and positively correlated with AIEC survival within MDMs from CD patients with or without anti-TNF, respectively. We observed a dose-dependent decrease of AIEC-LF82 survival after adjunction of anti-TNF within MDMs, inducing an increase of FLOT-1 and decrease of CHI3L1 mRNA levels. Neutralization of intra-macrophagic CHI3L1 protein using anti-CHI3L1 antibodies reduced AIEC survival within macrophages 6 h after infection [p < 0.05]. CONCLUSION Anti-TNF agents are able to restrict replication of pathobionts, such as AIEC, within macrophages by modulating FLOT-1 and CHI3L1 expression in CD patients.
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Affiliation(s)
- Clara Douadi
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France
| | - Emilie Vazeille
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Christophe Chambon
- INRAE, Plateforme d'Exploration du Métabolisme, composante protéomique (PFEMcp), Saint-Genès-Champanelle, France
| | - Michel Hébraud
- INRAE, Plateforme d'Exploration du Métabolisme, composante protéomique (PFEMcp), Saint-Genès-Champanelle, France.,Université Clermont Auvergne, INRAE, UMR Microbiologie Environnement digestif Santé (MEDiS), Saint-Genès-Champanelle, France
| | - Margot Fargeas
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France
| | - Marie Dodel
- Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Dilek Coban
- Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Bruno Pereira
- Biostatistic Unit, CHU Estaing, Clermont-Ferrand, France
| | - Aurélien Birer
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Centre National de Référence de la Résisitance aux antibiotiques, service de Bactériologie, CHU Gabriel-Montpied, Clermont-Ferrand, France
| | - Pierre Sauvanet
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Surgery and Oncology Digestive Department, CHU Estaing, Clermont-Ferrand, France
| | - Anthony Buisson
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France.,Gastroenterology Department, CHU Estaing, Clermont-Ferrand, France
| | - Nicolas Barnich
- Microbes, Intestin, Inflammation et Susceptibilité de l'Hôte (M2iSH), UMR 1071 Inserm/Université Clermont Auvergne, USC INRAE 2018, Clermont-Ferrand, France
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24
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Volkers AG, Appleton L, Gearry RB, Frampton CM, de Voogd FAE, Peters van Ton AM, Leach ST, Lemberg DA, Day AS. Fecal Calprotectin, Chitinase 3-Like-1, S100A12 and Osteoprotegerin as Markers of Disease Activity in Children with Crohn’s Disease. GASTROINTESTINAL DISORDERS 2022; 4:180-189. [DOI: 10.3390/gidisord4030017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/10/2023] Open
Abstract
Fecal calprotectin (FC), chitinase 3-like-1 protein (CHI3L1), S100A12 and osteoprotegerin (OPG) are biomarkers of intestinal inflammation. This cross-sectional study aimed to evaluate these biomarkers in a cohort of children with Crohn’s disease (CD) and compare them with other measures of disease activity. Stool samples from children with CD were used to measure FC, CHI3L1, S100A12 and OPG by enzyme-linked immunosorbent assay. Serum inflammatory markers were measured and pediatric CD disease activity index (PCDAI) scores calculated. The simple endoscopic score for CD (SES-CD) was reported for a subgroup who underwent ileocolonoscopy corresponding with the stool samples. Sixty-five children were recruited. Children in clinical remission had lower FC and CHI3L1 levels than those with active disease (FC: 277 vs. 1648 µg/g, p = 0.012; CHI3L1: 23 vs. 227 ng/g, p = 0.013). FC levels differed between patients with clinically active or inactive isolated ileal CD. Although FC and CHI3L1 levels correlated strongly (r = 0.83), none of the fecal markers correlated well with serum markers. Only FC and OPG correlated with SES-CD scores (r = 0.57 and r = 0.48, respectively). In conclusion, FC correlated with both endoscopic and clinical disease activity and was the only biomarker that differentiated between active and inactive ileal CD. CHI3L1 also predicted clinical disease activity and correlated highly with FC. Further investigation of the role of CHI3L1 is required.
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25
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Abstract
Although chitinase-3-like-1 (CHI3L1), predominately produced by epithelial cells and macrophages, is relevant to pulmonary disease in cystic fibrosis (CF), fecal levels have not yet been assessed in children with CF. Fecal CHI3L1 was measured with a commercial immunoassay using fecal samples provided by children with CF and healthy control (HC) children. Higher median (interquartile range) fecal CHI3L1 levels were seen in the 52 children with CF than in the 35 controls: 15.97 (3.34-50.53) ng/g versus 2.93 (2.13-9.27) ng/g ( P = 0.001). Fecal CHI3LI did not differ according to sex. In the children with CF, fecal CHI3L1 levels did not correlate with growth parameters nor were the levels affected by pancreatic insufficiency. Children with CF had higher fecal CHI3L1 levels, suggesting underlying gut inflammation. Further work is required to confirm the current findings and to ascertain the longer-term significance of elevated CHI3L1.
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26
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Devlin JR, Santus W, Mendez J, Peng W, Yu A, Wang J, Alejandro-Navarreto X, Kiernan K, Singh M, Jiang P, Mechref Y, Behnsen J. Salmonella enterica serovar Typhimurium chitinases modulate the intestinal glycome and promote small intestinal invasion. PLoS Pathog 2022; 18:e1010167. [PMID: 35482787 PMCID: PMC9049507 DOI: 10.1371/journal.ppat.1010167] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2021] [Accepted: 03/23/2022] [Indexed: 11/19/2022] Open
Abstract
Salmonella enterica serovar Typhimurium (S. Typhimurium) is one of the leading causes of food-borne illnesses worldwide. To colonize the gastrointestinal tract, S. Typhimurium produces multiple virulence factors that facilitate cellular invasion. Chitinases have been recently emerging as virulence factors for various pathogenic bacterial species, and the S. Typhimurium genome contains two annotated chitinases: STM0018 (chiA) and STM0233. However, the role of these chitinases during S. Typhimurium pathogenesis is unknown. The putative chitinase STM0233 has not been studied previously, and only limited data exists on ChiA. Chitinases typically hydrolyze chitin polymers, which are absent in vertebrates. However, chiA expression was detected in infection models and purified ChiA cleaved carbohydrate subunits present on mammalian surface glycoproteins, indicating a role during pathogenesis. Here, we demonstrate that expression of chiA and STM0233 is upregulated in the mouse gut and that both chitinases facilitate epithelial cell adhesion and invasion. S. Typhimurium lacking both chitinases showed a 70% reduction in invasion of small intestinal epithelial cells in vitro. In a gastroenteritis mouse model, chitinase-deficient S. Typhimurium strains were also significantly attenuated in the invasion of small intestinal tissue. This reduced invasion resulted in significantly delayed S. Typhimurium dissemination to the spleen and the liver, but chitinases were not required for systemic survival. The invasion defect of the chitinase-deficient strain was rescued by the presence of wild-type S. Typhimurium, suggesting that chitinases are secreted. By analyzing N-linked glycans of small intestinal cells, we identified specific N-acetylglucosamine-containing glycans as potential extracellular targets of S. Typhimurium chitinases. This analysis also revealed a differential abundance of Lewis X/A-containing glycans that is likely a result of host cell modulation due to the detection of S. Typhimurium chitinases. Similar glycomic changes elicited by chitinase deficient strains indicate functional redundancy of the chitinases. Overall, our results demonstrate that S. Typhimurium chitinases contribute to intestinal adhesion and invasion through modulation of the host glycome.
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Affiliation(s)
- Jason R. Devlin
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - William Santus
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - Jorge Mendez
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - Wenjing Peng
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States of America
| | - Aiying Yu
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States of America
| | - Junyao Wang
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States of America
| | - Xiomarie Alejandro-Navarreto
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - Kaitlyn Kiernan
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - Manmeet Singh
- Department of Pathology, University of Illinois Chicago, Chicago, Illinois, United States of America
| | - Peilin Jiang
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States of America
| | - Yehia Mechref
- Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, Texas, United States of America
| | - Judith Behnsen
- Department of Microbiology and Immunology, University of Illinois Chicago, Chicago, Illinois, United States of America
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27
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Mazur M, Włodarczyk J, Świerczyński M, Kordek R, Grzybowski MM, Olczak J, Fichna J. The Anti-Inflammatory Effect of Acidic Mammalian Chitinase Inhibitor OAT-177 in DSS-Induced Mouse Model of Colitis. Int J Mol Sci 2022; 23:ijms23042159. [PMID: 35216274 PMCID: PMC8875595 DOI: 10.3390/ijms23042159] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2022] [Revised: 02/04/2022] [Accepted: 02/11/2022] [Indexed: 12/02/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic and relapsing gastrointestinal disorders, where a significant proportion of patients are unresponsive or lose response to traditional and currently used therapies. In the current study, we propose a new concept for anti-inflammatory treatment based on a selective acidic mammalian chitinase (AMCase) inhibitor. The functions of chitinases remain unclear, but they have been shown to be implicated in the pathology of various inflammatory disorders regarding the lung (asthma, idiopathic pulmonary fibrosis) and gastrointestinal tract (IBD and colon cancer). The aim of the study is to investigate the impact of AMCase inhibitor (OAT-177) on the dextran sulfate sodium (DSS)-induced models of colitis. In the short-term therapeutic protocol, OAT-177 given intragastrically in a 30 mg/kg dose, twice daily, produced a significant (p < 0.001) anti-inflammatory effect, as shown by the macroscopic score. Additionally, OAT-177 significantly decreased TNF-α mRNA levels and MPO activity compared to DSS-only treated mice. Intraperitoneal administration of OAT-177 at a dose of 50 mg/kg caused statistically relevant reduction of the colon length. In the long-term therapeutic protocol, OAT-177 given intragastrically in a dose of 30 mg/kg, twice daily, significantly improved colon length and body weight compared to DSS-induced colitis. This is the first study proving that AMCase inhibitors may have therapeutic potential in the treatment of IBD.
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Affiliation(s)
- Marzena Mazur
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (M.M.); (J.W.); (M.Ś.)
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland; (M.M.G.); (J.O.)
| | - Jakub Włodarczyk
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (M.M.); (J.W.); (M.Ś.)
| | - Mikołaj Świerczyński
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (M.M.); (J.W.); (M.Ś.)
| | - Radzisław Kordek
- Department of Pathology, Faculty of Medicine, Medical University of Lodz, Pomorska 251, 92-213 Lodz, Poland;
| | - Marcin M. Grzybowski
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland; (M.M.G.); (J.O.)
| | - Jacek Olczak
- OncoArendi Therapeutics SA, Żwirki i Wigury 101, 02-089 Warsaw, Poland; (M.M.G.); (J.O.)
| | - Jakub Fichna
- Department of Biochemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; (M.M.); (J.W.); (M.Ś.)
- Correspondence: ; Tel.: +48-42-272-57-07
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28
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Biomarkers to Detect Early-Stage Colorectal Cancer. Biomedicines 2022; 10:biomedicines10020255. [PMID: 35203465 PMCID: PMC8869393 DOI: 10.3390/biomedicines10020255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 01/17/2022] [Accepted: 01/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer is a leading cause of mortality worldwide. The high incidence and the acceleration of incidence in younger people reinforces the need for better techniques of early detection. The use of noninvasive biomarkers has potential to more accurately inform how patients are prioritised for clinical investigation, which, in turn, may ultimately translate into improved survival for those subsequently found to have curable-stage CRC. This review surveys a wide range of CRC biomarkers that may (alone or in combination) identify symptomatic patients presenting in primary care who should be progressed for clinical investigation.
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29
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Huan W, Yandong L, Chao W, Sili Z, Jun B, Mingfang L, Yu C, Lefeng Q. YKL-40 Aggravates Early-Stage Atherosclerosis by Inhibiting Macrophage Apoptosis in an Aven-dependent Way. Front Cell Dev Biol 2021; 9:752773. [PMID: 34950656 PMCID: PMC8688858 DOI: 10.3389/fcell.2021.752773] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Accepted: 11/22/2021] [Indexed: 11/13/2022] Open
Abstract
Objective: programmed cell removal in atherosclerotic plaques plays a crucial role in retarding lesion progression. Macrophage apoptosis has a critical role in PrCR, especially in early-stage lesions. YKL-40 has been shown to be elevated as lesions develop and is closely related to macrophages. This study aimed to determine the effect of YKL-40 on regulating macrophage apoptosis and early-stage atherosclerosis progression. Research design and Methods: The correlations among the expression level of YKL-40, the area of early-stage plaque, and the macrophage apoptosis rate in plaques have been shown in human carotid atherosclerotic plaques through pathological and molecular biological detection. These results were successively confirmed in vivo (Ldlr−/- mice treated by YKL-40 recombinant protein/neutralizing antibody) and in vitro (macrophages that Ykl40 up-/down-expressed) experiments. The downstream targets were predicted by iTRAQ analysis. Results: In early-stage human carotid plaques and murine plaques, the YKL-40 expression level had a significant positive correlation with the area of the lesion and a significant negative correlation with the macrophage apoptosis rate. In vivo, the plaque area of aortic roots was significantly larger in the recomb-YKL-40 group than that in IgG group (p = 0.0247) and was significantly smaller in the anti-YKL-40 group than in the IgG group (p = 0.0067); the macrophage apoptosis rate of the plaque in aortic roots was significantly lower in the recomb-YKL-40 group than that in IgG group (p = 0.0018) and was higher in anti-YKL-40 group than that in VC group. In vitro, the activation level of caspase-9 was significantly lower in RAW264.7 with Ykl40 overexpressed than that in controls (p = 0.0054), while the expression level of Aven was significantly higher than that in controls (p = 0.0031). The apoptosis rate of RAW264.7 treated by recomb-YKL40 was significantly higher in the Aven down-regulated group than that in the control group (p < 0.001). The apoptosis inhibitor Aven was confirmed as the target molecule of YKL-40. Mechanistically, YKL-40 could inhibit macrophage apoptosis by upregulating Aven to suppress the activation of caspase-9. Conclusion: YKL-40 inhibits macrophage apoptosis by upregulating the apoptosis inhibitor Aven to suppress the activation of caspase-9, which may impede normal PrCR and promote substantial accumulation in early-stage plaques, thereby leading to the progression of atherosclerosis.
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Affiliation(s)
- Wei Huan
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Liu Yandong
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Wang Chao
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Zou Sili
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Bai Jun
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Liao Mingfang
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chen Yu
- Yueyang Hospital of Integrated Traditional Chinese Medicine & Clinical Research Institute of Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Qu Lefeng
- Department of Vascular and Endovascular Surgery, Second Affiliated Hospital of Naval Medical University, Shanghai, China
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30
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Chitinases and Chitinase-Like Proteins as Therapeutic Targets in Inflammatory Diseases, with a Special Focus on Inflammatory Bowel Diseases. Int J Mol Sci 2021; 22:ijms22136966. [PMID: 34203467 PMCID: PMC8268069 DOI: 10.3390/ijms22136966] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 06/22/2021] [Accepted: 06/24/2021] [Indexed: 11/17/2022] Open
Abstract
Chitinases belong to the evolutionarily conserved glycosyl hydrolase family 18 (GH18). They catalyze degradation of chitin to N-acetylglucosamine by hydrolysis of the β-(1-4)-glycosidic bonds. Although mammals do not synthesize chitin, they possess two enzymatically active chitinases, i.e., chitotriosidase (CHIT1) and acidic mammalian chitinase (AMCase), as well as several chitinase-like proteins (YKL-40, YKL-39, oviductin, and stabilin-interacting protein). The latter lack enzymatic activity but still display oligosaccharides-binding ability. The physiologic functions of chitinases are still unclear, but they have been shown to be involved in the pathogenesis of various human fibrotic and inflammatory disorders, particularly those of the lung (idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, sarcoidosis, and asthma) and the gastrointestinal tract (inflammatory bowel diseases (IBDs) and colon cancer). In this review, we summarize the current knowledge about chitinases, particularly in IBDs, and demonstrate that chitinases can serve as prognostic biomarkers of disease progression. Moreover, we suggest that the inhibition of chitinase activity may be considered as a novel therapeutic strategy for the treatment of IBDs.
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CHI3L1 promotes Staphylococcus aureus-induced osteomyelitis by activating p38/MAPK and Smad signaling pathways. Exp Cell Res 2021; 403:112596. [PMID: 33826950 DOI: 10.1016/j.yexcr.2021.112596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2020] [Revised: 03/21/2021] [Accepted: 04/01/2021] [Indexed: 12/26/2022]
Abstract
AIMS Staphylococcus aureus (S. aureus) is the most common causative bacterial pathogen involved in promoting infection-induced osteomyelitis, a disease resulting in severe bone degradation. In this study, we aimed to identify the mechanism behind inhibition of osteoclast survival and differentiation by CHI3L1, a lectin previously reported to regulate S. aureus-induced osteomyelitis. MAIN METHODS The role of CHI3L1 in osteoclast survival, proliferation, and differentiation was studied ex vivo using primary human bone marrow derived stem cells (HBMSCs) and transducing them with lentiviral expression vectors or shRNA knockdown constructs. Cell apoptosis was analyzed by flow cytometry using annexin V-fluorescein isothiocyanate/propidium iodide staining. Cell proliferation was assessed using alkaline phosphatase, Alcian Blue, and TRAP staining. The qRT-PCR was used to measure mRNA levels of osteoclast maturation markers, and western blotting was used to analyze protein expression. An in vivo murine model for osteomyelitis and microcomputed tomography analyses of infected femurs were used to study the effects of CHI3L1 on bone erosion. KEY FINDINGS Overexpression of CHI3L1 significantly reduced HBMSC cell viability, proliferation, and differentiation, and knockdown improved these effects in the presence of S. aureus infection. More specifically, CHI3L1 constitutively activated the p38/MAPK pathway to promote apoptosis. Furthermore, CHI3L1 induced activation of the Smad pathway by promoting phosphorylation of Smad-1/5 proteins. Finally, overexpression of CHI3L1 significantly induced bone erosion upon S. aureus infection in a murine osteomyelitis model, and knockdown of CHI3L1 significantly alleviated this effect. SIGNIFICANCE CHI3L1 played a vital role in osteoblast differentiation and proliferation by regulating the p38/MAPK and Smad signaling pathways to promote S. aureus-induced osteomyelitis.
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Nadalian B, Yadegar A, Houri H, Olfatifar M, Shahrokh S, Asadzadeh Aghdaei H, Suzuki H, Zali MR. Prevalence of the pathobiont adherent-invasive Escherichia coli and inflammatory bowel disease: a systematic review and meta-analysis. J Gastroenterol Hepatol 2021; 36:852-863. [PMID: 32929762 DOI: 10.1111/jgh.15260] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 07/08/2020] [Accepted: 09/07/2020] [Indexed: 12/21/2022]
Abstract
BACKGROUND AND AIM Escherichia coli pathobionts and particularly the adherent-invasive E. coli (AIEC) may play a putative role in initiating and maintaining the inflammatory process in the intestinal tissues of inflammatory bowel disease (IBD) patients, by providing stimulatory factors that trigger gut immune system activation. The aim of this study is to conduct a systematic review and meta-analysis to determine the prevalence of AIEC among patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS Electronic databases were searched up to February 2020 for relevant publications reporting the prevalence of AIEC in IBD patients. The prevalence rate of AIEC among CD and UC patients, the odds ratio (OR) and 95% confidence interval (CI) were calculated compared to non-IBD controls. RESULTS The final dataset included 12 studies, all investigating AIEC isolates from ileal/colonic specimens. The OR for prevalence of AIEC in CD patients was 3.27 (95% CI 1.79-5.9) compared with non-IBD controls. The overall pooled prevalence of AIEC among CD patients was 29% (95% CI 0.17-0.45), whereas this prevalence was calculated to be 9% (95% CI 0.03-0.19) in controls. Moreover, the prevalence of AIEC in UC subjects was calculated 12% (95% CI 0.01-0.34), while AIEC showed a prevalence of 5% (95% CI 0.0-0.17) among the controls. The OR for prevalence of AIEC in UC patients was 2.82 (95% CI 1.11-7.14) compared with controls. CONCLUSIONS There is a substantial increase in the prevalence of AIEC in IBD patients compared with controls. This review supports the growing evidence that AIEC could be involved in both CD and UC pathogenesis.
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Affiliation(s)
- Banafsheh Nadalian
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Abbas Yadegar
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamidreza Houri
- Foodborne and Waterborne Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Meysam Olfatifar
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Shabnam Shahrokh
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hidekazu Suzuki
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, School of Medicine, Tokai University, Isehara, Japan
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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A Review of Selected IBD Biomarkers: From Animal Models to Bedside. Diagnostics (Basel) 2021; 11:diagnostics11020207. [PMID: 33573291 PMCID: PMC7911946 DOI: 10.3390/diagnostics11020207] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 01/25/2021] [Accepted: 01/27/2021] [Indexed: 12/31/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a dysregulated inflammatory condition induced by multiple factors. The etiology of IBD is largely unknown, and the disease progression and prognosis are variable and unpredictable with uncontrolled disease behavior. Monitoring the status of chronic colitis closely is challenging for physicians, because the assessment of disease activity and severity require invasive methods. Using laboratory biomarkers may provide a useful alternative to invasive methods in the diagnosis and management of IBD. Furthermore, patients with ulcerative colitis or Crohn’s disease are also at risk of developing cancer. Annual colonoscopies can help lower the risk for developing colorectal cancer. However, laboratory biomarkers may also be helpful as non-invasive indicators in predicting treatment responses, improving prognosis, and predicting possible tumors. This review addresses selected laboratory biomarkers (including ANCA, chitinase 3-like 1, S100A12/RAGE, calprotectin, and TNF/TNFR2), which are identified by utilizing two well-accepted animal models of colitis, dextran sodium sulfate-induced and T cell receptor alpha knockout colitis models. In addition to being useful for monitoring disease severity, these biomarkers are associated with therapeutic strategies. The factors may regulate the initiation and perpetuation of inflammatory factors in the gut.
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Lim CJ, Nguyen PHD, Wasser M, Kumar P, Lee YH, Nasir NJM, Chua C, Lai L, Hazirah SN, Loh JJH, Khor LY, Yeong J, Lim TKH, Low AWX, Albani S, Chong TW, Chew V. Immunological Hallmarks for Clinical Response to BCG in Bladder Cancer. Front Immunol 2021; 11:615091. [PMID: 33584702 PMCID: PMC7879685 DOI: 10.3389/fimmu.2020.615091] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Accepted: 12/10/2020] [Indexed: 12/13/2022] Open
Abstract
Intravesical Bacillus Calmette-Guerin (BCG) is an effective immunotherapy for non-muscle invasive bladder cancer (NMIBC). However, recurrence and progression remain frequent warranting deeper insights into its mechanism. We herein comprehensively profiled blood and tissues obtained from NMIBC patients before, during and after BCG treatment using cytometry by time-of-flight (CyTOF) and RNA sequencing to identify the key immune subsets crucial for anti-tumor activity. We observed the temporal changes of peripheral immune subsets including NKT cells, central memory CD4+ T cells, CD8+ T cells and regulatory T cells (Treg) during the course of BCG. Gene expression analysis revealed enriched immune pathways involving in T cell activation and chemotaxis, as well as a more diversified T cell receptor repertoire in post-BCG tissues. Moreover, tissue multiplexed-immunofluorescence (mIF) showed baseline densities of non-Treg and CD8+PD-1+ T cells were predictive of response and better recurrence-free survival after BCG. Remarkably, post-BCG tissues from responders were found to be infiltrated with more active CD8+PD-1- T cells and non-Treg CD4+FOXP3- T cells; but increased exhausted CD8+PD-1+ T cells were found in non-responders. Taken together, we identified predictive biomarkers for response and uncovered the post-treatment expansion of exhausted PD-1+CD8+ T cells as key to BCG resistance, which could potentially be restored by combining with anti-PD-1 immunotherapy.
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Affiliation(s)
- Chun Jye Lim
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Phuong Hoang Diem Nguyen
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Martin Wasser
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Pavanish Kumar
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Yun Hua Lee
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Nurul Jannah Mohamed Nasir
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore.,Duke-NUS Medical School, Singapore, Singapore
| | - Camillus Chua
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Liyun Lai
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Sharifah Nur Hazirah
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Josh Jie Hua Loh
- Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Li Yan Khor
- Duke-NUS Medical School, Singapore, Singapore.,Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Joe Yeong
- Division of Pathology, Singapore General Hospital, Singapore, Singapore.,Institute of Molecular Cell Biology (IMCB), Agency of Science, Technology and Research (ASTAR), Singapore, Singapore
| | - Tony Kiat Hon Lim
- Duke-NUS Medical School, Singapore, Singapore.,Division of Pathology, Singapore General Hospital, Singapore, Singapore
| | | | - Salvatore Albani
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
| | - Tsung Wen Chong
- Duke-NUS Medical School, Singapore, Singapore.,Department of Urology, Singapore General Hospital, Singapore, Singapore
| | - Valerie Chew
- Translational Immunology Institute (TII), SingHealth-DukeNUS Academic Medical Centre, Singapore, Singapore
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Choo J, Heo G, Pothoulakis C, Im E. Posttranslational modifications as therapeutic targets for intestinal disorders. Pharmacol Res 2021; 165:105412. [PMID: 33412276 DOI: 10.1016/j.phrs.2020.105412] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/14/2020] [Accepted: 12/22/2020] [Indexed: 02/08/2023]
Abstract
A variety of biological processes are regulated by posttranslational modifications. Posttranslational modifications including phosphorylation, ubiquitination, glycosylation, and proteolytic cleavage, control diverse physiological functions in the gastrointestinal tract. Therefore, a better understanding of their implications in intestinal diseases, including inflammatory bowel disease, irritable bowel syndrome, celiac disease, and colorectal cancer would provide a basis for the identification of novel biomarkers as well as attractive therapeutic targets. Posttranslational modifications can be common denominators, as well as distinct biomarkers, characterizing pathological differences of various intestinal diseases. This review provides experimental evidence that identifies changes in posttranslational modifications from patient samples, primary cells, or cell lines in intestinal disorders, and a summary of carefully selected information on the use of pharmacological modulators of protein modifications as therapeutic options.
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Affiliation(s)
- Jieun Choo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Gwangbeom Heo
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea
| | - Charalabos Pothoulakis
- Section of Inflammatory Bowel Disease & Inflammatory Bowel Disease Center, Division of Digestive Diseases, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA
| | - Eunok Im
- College of Pharmacy, Pusan National University, Busan, 46241, Republic of Korea.
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Fenton CG, Taman H, Florholmen J, Sørbye SW, Paulssen RH. Transcriptional Signatures That Define Ulcerative Colitis in Remission. Inflamm Bowel Dis 2021; 27:94-105. [PMID: 32322884 PMCID: PMC7737162 DOI: 10.1093/ibd/izaa075] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND This study addresses whether existing specific transcriptional profiles can improve and support the current status of the definition of ulcerative colitis (UC) remission apart from the existing endoscopic, histologic, and laboratory scoring systems. For that purpose, a well-stratified UC patient population in remission was compared to active UC and control patients and was investigated by applying the next-generation technology RNA-Seq. METHODS Mucosal biopsies from patients in remission (n = 14), patients with active UC (n = 14), and healthy control patientss (n = 16) underwent whole-transcriptome RNA-Seq. Principal component analysis, cell deconvolution methods, gene profile enrichment, and pathway enrichment methods were applied to define a specific transcriptional signature of UC in remission. RESULTS Analyses revealed specific transcriptional signatures for UC in remission with increased expression of genes involved in O-glycosylation (MUC17, MUC3A, MUC5AC, MUC12, SPON1, B3GNT3), ephrin-mediated repulsion of cells (EFNB2E, EFNA3, EPHA10, EPHA1), GAP junction trafficking (TUBA1C, TUBA4A, TUBB4B, GJB3, CLTB), and decreased expression of several toll-like receptors (TLR1, TLR3, TLR5, TLR6). CONCLUSIONS This study reveals specific transcriptional signatures for remission. Partial restoration and improvement of homeostasis in the epithelial mucus layer and revival of immunological functions were observed. A clear role for bacterial gut flora composition can be implied. The results can be useful for the development of treatment strategies for UC in remission and may be useful targets for further investigations aiming to predict the outcome of UC in the future.
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Affiliation(s)
- Christopher G Fenton
- Department of Clinical Medicine,Genomics Support Centre Tromsø, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Hagar Taman
- Department of Clinical Medicine,Genomics Support Centre Tromsø, UiT-The Arctic University of Norway, Tromsø, Norway
- Department of Clinical Medicine, Gastroenterology and Nutrition Research Group, UiT-The Arctic University of Norway, Tromsø, Norway
| | - Jon Florholmen
- Department of Clinical Medicine, Gastroenterology and Nutrition Research Group, UiT-The Arctic University of Norway, Tromsø, Norway
- Department of Medical Gastroenterology, University Hospital of North Norway, Tromsø, Norway
| | - Sveinung W Sørbye
- §Department of Clinical Pathology, University Hospital of North Norway, Tromsø, Norway
| | - Ruth H Paulssen
- Department of Clinical Medicine,Genomics Support Centre Tromsø, UiT-The Arctic University of Norway, Tromsø, Norway
- Department of Clinical Medicine, Gastroenterology and Nutrition Research Group, UiT-The Arctic University of Norway, Tromsø, Norway
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Zhu W, Lönnblom E, Förster M, Johannesson M, Tao P, Meng L, Lu S, Holmdahl R. Natural polymorphism of Ym1 regulates pneumonitis through alternative activation of macrophages. SCIENCE ADVANCES 2020; 6:6/43/eaba9337. [PMID: 33087360 PMCID: PMC7577715 DOI: 10.1126/sciadv.aba9337] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 09/02/2020] [Indexed: 05/12/2023]
Abstract
We have positionally cloned the Ym1 gene, with a duplication and a promoter polymorphism, as a major regulator of inflammation. Mice with the RIIIS/J haplotype, with the absence of Ym1 expression, showed reduced susceptibility to mannan-enhanced collagen antibody-induced arthritis and to chronic arthritis induced by intranasal exposure of mannan. Depletion of lung macrophages alleviated arthritis, whereas intranasal supplement of Ym1 protein to Ym1-deficient mice reversed the disease, suggesting a key role of Ym1 for inflammatory activity by lung macrophages. Ym1-deficient mice with pneumonitis had less eosinophil infiltration, reduced production of type II cytokines and IgG1, and skewing of macrophages toward alternative activation due to enhanced STAT6 activation. Proteomics analysis connected Ym1 polymorphism with changed lipid metabolism. Induced PPAR-γ and lipid metabolism in Ym1-deficient macrophages contributed to cellular polarization. In conclusion, the natural polymorphism of Ym1 regulates alternative activation of macrophages associated with pulmonary inflammation.
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Affiliation(s)
- Wenhua Zhu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061 Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, 710061 Xi'an, China
- The National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, 710004 Xi'an, China
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
| | - Erik Lönnblom
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
| | - Michael Förster
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
| | - Martina Johannesson
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
| | - Pei Tao
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061 Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, 710061 Xi'an, China
| | - Liesu Meng
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061 Xi'an, China.
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, 710061 Xi'an, China
- The National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, 710004 Xi'an, China
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
| | - Shemin Lu
- Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 710061 Xi'an, China
- Key Laboratory of Environment and Genes Related to Diseases (Xi'an Jiaotong University), Ministry of Education of China, 710061 Xi'an, China
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
| | - Rikard Holmdahl
- The National Local Joint Engineering Research Center of Biodiagnostics and Biotherapy, the Second Affiliated Hospital of Xi'an Jiaotong University, 710004 Xi'an, China.
- Section for Medical Inflammation Research, Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm 171 77, Sweden
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Chitinase-3 like-protein-1 function and its role in diseases. Signal Transduct Target Ther 2020; 5:201. [PMID: 32929074 PMCID: PMC7490424 DOI: 10.1038/s41392-020-00303-7] [Citation(s) in RCA: 275] [Impact Index Per Article: 55.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2020] [Revised: 07/28/2020] [Accepted: 08/20/2020] [Indexed: 12/12/2022] Open
Abstract
Non-enzymatic chitinase-3 like-protein-1 (CHI3L1) belongs to glycoside hydrolase family 18. It binds to chitin, heparin, and hyaluronic acid, and is regulated by extracellular matrix changes, cytokines, growth factors, drugs, and stress. CHI3L1 is synthesized and secreted by a multitude of cells including macrophages, neutrophils, synoviocytes, chondrocytes, fibroblast-like cells, smooth muscle cells, and tumor cells. It plays a major role in tissue injury, inflammation, tissue repair, and remodeling responses. CHI3L1 has been strongly associated with diseases including asthma, arthritis, sepsis, diabetes, liver fibrosis, and coronary artery disease. Moreover, following its initial identification in the culture supernatant of the MG63 osteosarcoma cell line, CHI3L1 has been shown to be overexpressed in a wealth of both human cancers and animal tumor models. To date, interleukin-13 receptor subunit alpha-2, transmembrane protein 219, galectin-3, chemo-attractant receptor-homologous 2, and CD44 have been identified as CHI3L1 receptors. CHI3L1 signaling plays a critical role in cancer cell growth, proliferation, invasion, metastasis, angiogenesis, activation of tumor-associated macrophages, and Th2 polarization of CD4+ T cells. Interestingly, CHI3L1-based targeted therapy has been increasingly applied to the treatment of tumors including glioma and colon cancer as well as rheumatoid arthritis. This review summarizes the potential roles and mechanisms of CHI3L1 in oncogenesis and disease pathogenesis, then posits investigational strategies for targeted therapies.
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Al Azzaz J, Al Tarraf A, Heumann A, Da Silva Barreira D, Laurent J, Assifaoui A, Rieu A, Guzzo J, Lapaquette P. Resveratrol Favors Adhesion and Biofilm Formation of Lacticaseibacillus paracasei subsp. paracasei Strain ATCC334. Int J Mol Sci 2020; 21:ijms21155423. [PMID: 32751457 PMCID: PMC7432909 DOI: 10.3390/ijms21155423] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2020] [Revised: 07/21/2020] [Accepted: 07/28/2020] [Indexed: 12/21/2022] Open
Abstract
Bacterial strains of the Lactobacillaceae family are widely used as probiotics for their multifaceted potential beneficial properties. However, no official recommendations for their clinical use exist since, in many cases, oral administrations of these bacteria displayed limited beneficial effects in human. Additional research is thus needed to improve the efficiency of existing strains with strong potential. In this context, we assess in vitro the effects of nine polyphenols to stimulate biofilm formation by lactobacilli, a feature enhancing their functionalities. Among these polyphenols, we identify trans-Resveratrol (referred to hereafter as Resveratrol) as a potent inducer of biofilm formation by Lacticaseibacillus paracasei (formerly designated as Lactobacillus paracasei) ATCC334 strain. This effect is strain-dependent and relies on the enhancement of L. paracasei adhesion to abiotic and biotic surfaces, including intestinal epithelial cells. Mechanistically, Resveratrol modify physico-chemical properties of the bacterial surface and thereby enhances L. paracasei aggregation, subsequently facilitating adhesion and biofilm development. Together, our in vitro data demonstrate that Resveratrol might be used to modulate the behavior of Lactobacilli with probiotic properties. Combination of probiotics and polyphenols could be considered to enhance the probiotic functionalities in further in vivo studies.
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Affiliation(s)
- Jana Al Azzaz
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
- Muséum National d’Histoire Naturelle (MNHN), Centre National de la Recherche Scientifique, UMR7245, Molécules de Communication et Adaptation des Microorganismes (MCAM), 75005 Paris, France
| | - Alissar Al Tarraf
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
| | - Arnaud Heumann
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
| | - David Da Silva Barreira
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
| | - Julie Laurent
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
| | - Ali Assifaoui
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
| | - Aurélie Rieu
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
| | - Jean Guzzo
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
- Correspondence: (J.G.); (P.L.)
| | - Pierre Lapaquette
- Université de Bourgogne Franche-Comté (UBFC), AgroSup Dijon, F-21000 Dijon, France; (J.A.A.); (A.A.T.); (A.H.); (D.D.S.B.); (J.L.); (A.A.); (A.R.)
- Correspondence: (J.G.); (P.L.)
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The expression levels of CHI3L1 and IL15Rα correlate with TGM2 in duodenum biopsies of patients with celiac disease. Inflamm Res 2020; 69:925-935. [PMID: 32500186 DOI: 10.1007/s00011-020-01371-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 05/13/2020] [Accepted: 06/02/2020] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVE AND DESIGN Celiac disease (CD) is an intestinal inflammatory disorder of the small intestine. Gliadins are a component of gluten and there are three main types (α, γ, and ω). Recent studies indicate that gliadin peptides are able to activate an innate immune response. IL15 is a major mediator of the innate immune response and is involved in the early alteration of CD mucosa. The chitinase molecules are highly expressed by the innate immune cells during the inflammatory processes. MATERIAL OR SUBJECTS We analyzed several microarray datasets of PBMCs and duodenum biopsies of CD patients and healthy control subjects (HCs). We verified the modulation CHI3L1 in CD patients and correlated the expression levels to the IL15, IL15Rα, TGM2, IFNγ, and IFNGR1/2. Duodenal biopsy samples belonged to nine active and nine treated children patients (long-term effects of gliadin), and 17 adult CD patients and 10 adults HCs. We also selected 169 samples of PBMCs from 127 CD patients on adherence to a gluten-free diet (GFD) for at least 2 years and 44 HCs. RESULTS Our analysis showed that CHI3L1 and IL15Rα were significantly upregulated in adult and children's celiac duodenum biopsies. In addition, the two genes were correlated significantly both in children than in adults CD duodenum biopsies. No significant modulation was observed in PBMCs of adult CD patients compared to the HCs. The correlation analysis of the expression levels of CHI3L1 and IL15Rα compared to TGM showed significant values both in adults and in children duodenal biopsies. Furthermore, the IFNγ expression levels were positively correlated with CHI3L1 and IL15Rα. Receiver operating characteristic (ROC) analysis confirmed the diagnostic ability of CHI3L1 and IL15Rα to discriminate CD from HCs. CONCLUSION Our data suggest a role for CHI3L1 underlying the pathophysiology of CD and represent a starting point aiming to inspire new investigation that proves the possible use of CHI3L1 as a diagnostic factor and therapeutic target.
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Chervy M, Barnich N, Denizot J. Adherent-Invasive E. coli: Update on the Lifestyle of a Troublemaker in Crohn's Disease. Int J Mol Sci 2020; 21:E3734. [PMID: 32466328 PMCID: PMC7279240 DOI: 10.3390/ijms21103734] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/22/2020] [Accepted: 05/24/2020] [Indexed: 12/12/2022] Open
Abstract
Besides genetic polymorphisms and environmental factors, the intestinal microbiota is an important factor in the etiology of Crohn's disease (CD). Among microbiota alterations, a particular pathotype of Escherichia coli involved in the pathogenesis of CD abnormally colonizes the intestinal mucosa of patients: the adherent-invasive Escherichia coli (AIEC) pathobiont bacteria, which have the abilities to adhere to and to invade intestinal epithelial cells (IECs), as well as to survive and replicate within macrophages. AIEC have been the subject of many studies in recent years to unveil some genes linked to AIEC virulence and to understand the impact of AIEC infection on the gut and consequently their involvement in CD. In this review, we describe the lifestyle of AIEC bacteria within the intestine, from the interaction with intestinal epithelial and immune cells with an emphasis on environmental and genetic factors favoring their implantation, to their lifestyle in the intestinal lumen. Finally, we discuss AIEC-targeting strategies such as the use of FimH antagonists, bacteriophages, or antibiotics, which could constitute therapeutic options to prevent and limit AIEC colonization in CD patients.
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Affiliation(s)
- Mélissa Chervy
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), 63001 Clermont-Ferrand, France; (M.C.); (N.B.)
| | - Nicolas Barnich
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), 63001 Clermont-Ferrand, France; (M.C.); (N.B.)
- Institut Universitaire de Technologie, Génie Biologique, 63172 Aubière, France
| | - Jérémy Denizot
- Université Clermont Auvergne, Inserm U1071, USC-INRAE 2018, Microbes, Intestin, Inflammation et Susceptibilité de l’Hôte (M2iSH), 63001 Clermont-Ferrand, France; (M.C.); (N.B.)
- Institut Universitaire de Technologie, Génie Biologique, 63172 Aubière, France
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de Bruyn M, Ringold R, Martens E, Ferrante M, Van Assche G, Opdenakker G, Dukler A, Vermeire S. The Ulcerative Colitis Response Index for Detection of Mucosal Healing in Patients Treated With Anti-tumour Necrosis Factor. J Crohns Colitis 2020; 14:176-184. [PMID: 31628842 DOI: 10.1093/ecco-jcc/jjz125] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
BACKGROUND Surrogate markers that accurately detect mucosal healing [MH] in patients with ulcerative colitis [UC] are urgently needed. Several stool neutrophil-related proteins are currently used as biomarkers for MH. However, the sensitivity and specificity are not sufficient to avoid unnecessary endoscopic evaluations. METHODS Novel serum neutrophil-related markers (neutrophil gelatinase B-associated lipocalin and matrix metalloproteinase-9 [NGAL-MMP-9 complex], cathelicidin LL-37 and chitinase 3-like 1 [CHI3L1]), together with C-reactive protein [CRP] and neutrophil counts were studied. Serum samples were obtained from 176 anti-tumour necrosis factor [anti-TNF]-treated UC patients (145 infliximab [IFX] and 31 adalimumab [ADM]) at baseline and after a median of 9.5 weeks. All patients had active disease prior to treatment (Mayo endoscopic subscore [MES] ≥ 2), and MH was defined as MES ≤ 1. Serum was also obtained from 75 healthy controls. Binary logistic regression analysis was used to generate the Ulcerative Colitis Response Index [UCRI]. The performance of individual markers and UCRI was tested with receiver operating characteristic analysis. RESULTS All neutrophil-related markers were significantly higher in active UC patients compared to healthy controls. In the IFX cohort, CRP, NGAL-MMP-9, CHI3L1 and neutrophil count decreased significantly after treatment and all marker levels were significantly lower in healers compared to non-healers following IFX. In the ADM cohort, CRP, NGAL-MMP-9, CHI3L1 and neutrophil count decreased significantly only in healers. UCRI [including CRP, CHI3L1, neutrophil count and LL-37] accurately detected MH in both IFX-treated (area under the curve [AUC] = 0.83) and ADM-treated [AUC = 0.79] patients. CONCLUSIONS The new UCRI index accurately detects MH after treatment with IFX and ADM. This panel is useful for monitoring MH in UC patients under anti-TNF treatment. PODCAST This article has an associated podcast which can be accessed at https://academic.oup.com/ecco-jcc/pages/podcast.
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Affiliation(s)
- Magali de Bruyn
- Translational Research Centre for GastroIntestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.,Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Randy Ringold
- Kepler Diagnostics, Inc., Simi Valley, California, USA
| | - Erik Martens
- Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | - Marc Ferrante
- Translational Research Centre for GastroIntestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Gert Van Assche
- Translational Research Centre for GastroIntestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
| | - Ghislain Opdenakker
- Rega Institute for Medical Research, Department of Microbiology and Immunology, KU Leuven, Leuven, Belgium
| | | | - Séverine Vermeire
- Translational Research Centre for GastroIntestinal Disorders (TARGID), Department of Chronic Diseases, Metabolism and Ageing (CHROMETA), KU Leuven, Leuven, Belgium.,University Hospitals Leuven, Department of Gastroenterology and Hepatology, Leuven, Belgium
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Wang R, Xu C, Zhong H, Hu B, Wei L, Liu N, Zhang Y, Shi Q, Wang C, Qi M, Gu Y, Shen X, Tian Y, Liu Y, Cao P, Chen H, Yuan W. Inflammatory-sensitive CHI3L1 protects nucleus pulposus via AKT3 signaling during intervertebral disc degeneration. FASEB J 2020; 34:3554-3569. [PMID: 31997395 DOI: 10.1096/fj.201902096r] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Revised: 10/06/2019] [Accepted: 10/23/2019] [Indexed: 01/08/2023]
Abstract
Intervertebral disc degeneration (IDD) is the main cause of low back pain and the mechanism of which is far from fully revealed. Although inflammation directed nucleus pulposus (NP) extracellular matrix metabolism dysregulation is known to be the main cause of the degeneration process, few is known about the protective factors. Using high-throughput label-free proteomics, we found that inflammation-related autocrine factor Chitinase-3-like protein 1 (CHI3L1, or YKL-40) is highly expressed in the NP cells during degeneration. Immunohistochemical analysis show that the expression of CHI3L1 is NP tissue specific, and increase significantly during degeneration. Overexpression of CHI3L1 significantly decrease the catabolism, and increase the anabolism of extracellular matrix. Knockdown of CHI3L1 using siRNAs show the opposite results, which imply that the protective role of CHI3L1 in IDD. Using high-throughput RNA sequencing and functional analyses, we find that AKT3 expression and its phosphorylation is mainly regulated by CHI3L1. And lastly, the mechanism of which is also validated using human and mouse degenerated NP tissues. In summary, our findings show that the inflammation-related autocrine factor CHI3L1 is NP specific, and it protects IDD by promoting the AKT3 signaling, which may serve as a potential therapeutic target in intervertebral disc degeneration.
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Affiliation(s)
- Ruizhe Wang
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Chen Xu
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Huajian Zhong
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Bo Hu
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Leixin Wei
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Ning Liu
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Yizhi Zhang
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Qianghui Shi
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Chen Wang
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Min Qi
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Yifei Gu
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Xiaolong Shen
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Ye Tian
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Yang Liu
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Peng Cao
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Huajiang Chen
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
| | - Wen Yuan
- Spine Center, Department of Orthopedics, Changzheng Hospital Affiliated to Second Military Medical University, Shanghai, China
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Kim EG, Kim MN, Hong JY, Lee JW, Kim SY, Kim KW, Lee CG, Elias JA, Song TW, Sohn MH. Chitinase 3-Like 1 Contributes to Food Allergy via M2 Macrophage Polarization. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2020; 12:1012-1028. [PMID: 32935492 PMCID: PMC7492506 DOI: 10.4168/aair.2020.12.6.1012] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 05/20/2020] [Accepted: 05/24/2020] [Indexed: 12/13/2022]
Abstract
Purpose Food allergy is a hypersensitive immune response to specific food proteins. Chitinase 3-like 1 (CHI3L1, also known as YKL-40 in humans or BRP-39 in mice) is associated with various chronic diseases, such as cancer, rheumatoid arthritis, and allergic disease. CHI3L1 is involved in allergen sensitization and type 2 helper T (Th2) inflammation, but the role of CHI3L1 in food allergy remains unclear. In this study, we sought to investigate the role of CHI3L1 in the development of food allergy. Methods We measured serum levels of CHI3L1 in food allergic patients. Food allergy was induced in wild-type (WT) and CHI3L1 null mutant (CHI3L1−/−) BALB/c mice with ovalbumin (OVA). We investigated Th2 immune responses, M2 macrophage polarization, and mitogen-activated protein kinase (MAPK)/phosphoinositide 3-kinase (PI3K) signaling pathways, and also performed transcriptome analysis. Results Serum levels of CHI3L1 were significantly higher in children with food allergy compared with those in healthy controls. Furthermore, CHI3L1 expression levels were elevated in WT mice after OVA treatment. Food allergy symptoms, immunoglobulin E levels, Th2 cytokine production, and histological injury were attenuated in food allergy-induced CHI3L1−/− mice compared with those in food allergy-induced WT mice. CHI3L1 expression was increased in OVA-treated WT intestinal macrophages and caused M2 macrophage polarization. Furthermore, CHI3L1 was involved in the extracellular signal-regulated kinases (ERK) and AKT signaling pathways and was associated with immune response and lipid metabolism as determined through transcriptome analysis. Conclusions CHI3L1 plays a pivotal role in Th2 inflammation and M2 macrophage polarization through MAPK/ERK and PI3K/AKT phosphorylation in food allergy.
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Affiliation(s)
- Eun Gyul Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Mi Na Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jung Yeon Hong
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Jae Woo Lee
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Soo Yeon Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Kyung Won Kim
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea
| | - Chun Geun Lee
- Molecular Microbiology and Immunology, Brown University, Providence, RI, USA.,Department of Internal Medicine, Hanyang University, Seoul, Korea
| | - Jack A Elias
- Molecular Microbiology and Immunology, Brown University, Providence, RI, USA
| | - Tae Won Song
- Department of Pediatrics, Ilsan Paik Hospital, Inje University College of Medicine, Goyang, Korea.
| | - Myung Hyun Sohn
- Department of Pediatrics, Severance Hospital, Institute of Allergy, Institute for Immunology and Immunological Diseases, Brain Korea 21 PLUS Project for Medical Science, Yonsei University College of Medicine, Seoul, Korea.
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Yano A. IL-10-Producing Potential Treg Precursor in Placenta. Kurume Med J 2019; 65:169-176. [PMID: 31723081 DOI: 10.2739/kurumemedj.ms654008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The maternal immune system needs to be tolerant of allogeneic fetal tissue for reproductive success. The regulatory immune cell network plays an essential role in maintaining maternal tolerance to the fetus. We herein demonstrate in a green fluorescent protein (GFP)/IL-10 reporter mouse system that unique IL-10-expressing cells exist presumably in chorionic villi within the placenta. Flow cytometric analysis revealed that these IL-10- expressing cells exhibit a unique CD19 negative, CD3 negative, and B220 positive phenotype. Interestingly, these cells were enriched during in vitro culture, but well-known stimuli for T cells and B cells failed to enhance their growth, suggesting that the CD19- CD3- B220+ cells were self renewing. Unexpectedly, in an adoptive cell trans fer experiment, IL-10 production was detected in Sca-1+ CD4+ CD25+ regulatory T cells (Treg). To our knowledge, this is the first report to identify IL-10-producing CD19- CD3- B220+ cells in the fetus. These cells may rep resent a potential progenitor of Sca-1+ Treg or pluripotent precursor cells for immune tolerance.
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Affiliation(s)
- Arisa Yano
- Department of Immunology, Kurume University of School of Medicine
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Macrophages Inability to Mediate Adherent-Invasive E. coli Replication is Linked to Autophagy in Crohn's Disease Patients. Cells 2019; 8:cells8111394. [PMID: 31694333 PMCID: PMC6912674 DOI: 10.3390/cells8111394] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2019] [Revised: 10/24/2019] [Accepted: 10/30/2019] [Indexed: 12/28/2022] Open
Abstract
The macrophages from Crohn’s Disease (CD) patients are defective to control the replication of CD-associated adherent-invasive E. coli (AIEC). We aimed to identify the host factors associated with AIEC replication focusing on polymorphisms related to autophagy. Peripheral blood monocyte-derived macrophages (MDM), obtained from 95 CD patient, 30 ulcerative colitis (UC) patients and 15 healthy subjects, were genotyped for several CD-associated polymorphisms. AIEC bacteria survival increased within MDM from CD patients compared to UC (p = 0.0019). AIEC bacteria survival increased in patients with CD-associated polymorphism IRGM (p = 0.05) and reduced in those with CD-associated polymorphisms XBP-1 (p = 0.026) and ULK-1 (p = 0.033). AIEC infection led to an increase of pro-inflammatory cytokines IL-1β (p < 0.0001) and TNF-α (p < 0.0001) in CD macrophages. ULK-1 expression increased in AIEC-infected MDM from CD patients compared to MDM from UC patients or healthy subjects (p = 0.0056) and correlated with AIEC survival (p = 0.0013). Moreover, the expression of ULK-1 phosphorylation on Serine 757 decreased following to AIEC infection (p < 0.0001). Short-term silencing of ULK-1 and IRGM genes restricted and promote, respectively, AIEC survival within MDM (p = 0.0018 and p = 0.0291). In conclusion, the macrophage defect to mediate AIEC clearance in CD patients is linked to polymorphisms related to autophagy such as IRGM and ULK-1.
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Holtan SG, Shabaneh A, Betts BC, Rashidi A, MacMillan ML, Ustun C, Amin K, Vaughn BP, Howard J, Khoruts A, Arora M, DeFor TE, Johnson D, Blazar BR, Weisdorf DJ, Wang J. Stress responses, M2 macrophages, and a distinct microbial signature in fatal intestinal acute graft-versus-host disease. JCI Insight 2019; 5:129762. [PMID: 31393854 DOI: 10.1172/jci.insight.129762] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Steroid-refractory intestinal acute graft-versus-host disease (aGVHD) is a frequently fatal condition with little known about mechanisms driving failed steroid responses in gut mucosa. To uncover novel molecular insights in steroid-refractory aGVHD, we compared gene expression profiles of rectosigmoid biopsies from patients at diagnosis of clinical stage 3-4 lower intestinal aGVHD (N=22), to repeat biopsies when the patients became steroid refractory (N=22), and normal controls (N=10). We also performed single gene analyses of factors associated with tolerance (programmed death ligand-1 [PDL1], indoleamine 2,3 dioxygenase [IDO1], and T cell immunoreceptor with Ig and ITIM domains [TIGIT]) and found that significantly higher expression levels of these aGVHD inhibitory genes (PDL1, IDO1, TIGIT) at aGVHD onset became decreased in the steroid-refractory state. We examined genes triggered by microbial ligands to stimulate gut repair, amphiregulin (AREG) and the aryl hydrocarbon receptor (AhR), and found that both AREG and AhR gene expression levels were increased at aGVHD onset and remained elevated in steroid-refractory aGVHD. We also identified higher expression levels of metallothioneines, metal-binding enzymes induced in stress responses, and M2 macrophage genes in steroid-refractory aGVHD. We observed no differences in T-cell subsets between onset and steroid-refractory aGVHD. Patients with a rapidly fatal course showed greater DNA damage and a distinct microbial signature at aGVHD onset, whereas patients with more prolonged survival exhibited a gene expression profile consistent with activation of Smoothened. Our results extend the paradigm beyond T cell-centric therapies for steroid-refractory GI aGVHD and highlight new mechanisms for therapeutic exploration.
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Affiliation(s)
| | | | - Brian C Betts
- Blood and Marrow Transplant Program, Department of Medicine
| | - Armin Rashidi
- Blood and Marrow Transplant Program, Department of Medicine
| | - Margaret L MacMillan
- Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Celalletin Ustun
- Rush University Blood and Marrow Transplant Program, Chicago, Illinois, USA
| | | | | | - Justin Howard
- Division of Gastroenterology, Department of Medicine
| | | | - Mukta Arora
- Blood and Marrow Transplant Program, Department of Medicine
| | | | | | - Bruce R Blazar
- Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | | | - Jinhua Wang
- Cancer Bioinformatics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota, USA
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Yeo IJ, Lee CK, Han SB, Yun J, Hong JT. Roles of chitinase 3-like 1 in the development of cancer, neurodegenerative diseases, and inflammatory diseases. Pharmacol Ther 2019; 203:107394. [PMID: 31356910 DOI: 10.1016/j.pharmthera.2019.107394] [Citation(s) in RCA: 86] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2019] [Indexed: 02/07/2023]
Abstract
Chitinase 3-like 1 (CHI3L1) is a secreted glycoprotein that mediates inflammation, macrophage polarization, apoptosis, and carcinogenesis. The expression of CHI3L1 is strongly increased by various inflammatory and immunological conditions, including rheumatoid arthritis, multiple sclerosis, Alzheimer's disease, and several cancers. However, its physiological and pathophysiological roles in the development of cancer and neurodegenerative and inflammatory diseases remain unclear. Several studies have reported that CHI3L1 promotes cancer proliferation, inflammatory cytokine production, and microglial activation, and that multiple receptors, such as advanced glycation end product, syndecan-1/αVβ3, and IL-13Rα2, are involved. In addition, the pro-inflammatory action of CHI3L1 may be mediated via the protein kinase B and phosphoinositide-3 signaling pathways and responses to various pro-inflammatory cytokines, including tumor necrosis factor-α, interleukin-1β, interleukin-6, and interferon-γ. Therefore, CHI3L1 could contribute to a vast array of inflammatory diseases. In this article, we review recent findings regarding the roles of CHI3L1 and suggest therapeutic approaches targeting CHI3L1 in the development of cancers, neurodegenerative diseases, and inflammatory diseases.
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Affiliation(s)
- In Jun Yeo
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Chong-Kil Lee
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Sang-Bae Han
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea
| | - Jaesuk Yun
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea.
| | - Jin Tae Hong
- College of Pharmacy and Medical Research Center, Chungbuk National University, 194-31, Osongsaengmyeong 1-ro, Osong-eup, Cheongju-si, Chungbuk 28160, Republic of Korea.
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Deutschmann C, Sowa M, Murugaiyan J, Roesler U, Röber N, Conrad K, Laass MW, Bogdanos D, Sipeki N, Papp M, Rödiger S, Roggenbuck D, Schierack P. Identification of Chitinase-3-Like Protein 1 as a Novel Neutrophil Antigenic Target in Crohn's Disease. J Crohns Colitis 2019; 13:894-904. [PMID: 30753386 PMCID: PMC6657965 DOI: 10.1093/ecco-jcc/jjz012] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND AND AIMS There is an increasing incidence of inflammatory bowel disease [IBD]. Autoimmune responses are involved in the pathophysiology of IBD, but their underlying pathways and target antigens have not yet been fully elucidated. METHODS Autoantigenic targets in IBD were identified after separation of whole cell proteins isolated from neutrophils using two-dimensional electrophoresis and matrix assisted laser desorption ionization - time of flight mass spectrometry-based protein identification of the spots that displayed Western blotting signals with anti-neutrophil cytoplasmic antibody-positive sera. The prevalence of IgG, IgA and secretory IgA [sIgA] to chitinase 3-like protein 1 [CHI3L1] was analysed by enzyme-linked immunosorbent assays using recombinant CHI3L1 in 110 patients with Crohn's disease [CD], 95 with ulcerative colitis [UC], 126 with coeliac disease [CeD] and 86 healthy controls [HCs]. RESULTS The 18-glycosylhydrolase family member CHI3L1 was identified as a neutrophil autoantigenic target. CD patients displayed significantly higher levels of IgG to CHI3L1 than patients with UC and CeD (p < 0.0001, respectively). IgA and sIgA to CHI3L1 was significantly higher in CD than in UC, CeD and HCs [p < 0.0001, respectively]. IgA and sIgA to CHI3L1 demonstrated the highest prevalence in CD [25.5%, 28/110; and 41.8%%, 46/110] compared to HCs [2.3%, 2/86; and 4.7%%, 4/86; p = 0.0015 and p < 0.0001] and are associated with a more complicated progression of CD. CONCLUSION CHI3L1 is a novel neutrophil autoantigenic target in CD. IgA and sIgA to CHI3L1 may serve as novel markers for CD and may facilitate the serological diagnosis of IBD.
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Affiliation(s)
- Claudia Deutschmann
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany
| | - Mandy Sowa
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany,Medipan/GA Generic Assays GmbH, Ludwig-Erhard-Ring, Dahlewitz, Berlin, Germany
| | - Jayaseelan Murugaiyan
- Institute for Animal Hygiene and Environmental Health, Freie Universität Berlin, Centre for Infectious Medicine, Robert-von-Ostertag-Str., Berlin, Germany,Department of Biotechnology, SRM University-AP, Amaravati, India
| | - Uwe Roesler
- Institute for Animal Hygiene and Environmental Health, Freie Universität Berlin, Centre for Infectious Medicine, Robert-von-Ostertag-Str., Berlin, Germany
| | - Nadja Röber
- Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße, Dresden, Germany
| | - Karsten Conrad
- Institute of Immunology, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße, Dresden, Germany
| | - Martin W Laass
- Children’s Hospital, Medical Faculty Carl Gustav Carus, Technical University Dresden, Fetscherstraße, Dresden, Germany
| | - Dimitrios Bogdanos
- Department of Rheumatology, School of Health Sciences, University of Thessaly, Larissa, Greece
| | - Nora Sipeki
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Nagyerdei krt., Debrecen, Hungary
| | - Maria Papp
- Department of Internal Medicine, Division of Gastroenterology, Faculty of Medicine, University of Debrecen, Nagyerdei krt., Debrecen, Hungary
| | - Stefan Rödiger
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany
| | - Dirk Roggenbuck
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany,Medipan/GA Generic Assays GmbH, Ludwig-Erhard-Ring, Dahlewitz, Berlin, Germany
| | - Peter Schierack
- Institute of Biotechnology, Faculty Environment and Natural Sciences, Brandenburg University of Technology Cottbus-Senftenberg, Universitätsplatz, Senftenberg, Germany,Corresponding author: Prof. Dr Peter Schierack, Faculty Environment and Natural Sciences, Brandenburg University of Technology, Universitätsplatz 1, 01968 Senftenberg, Germany. Tel: +49 (0) 3573 85 932; Fax: +49 (0) 3573 85 909;
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Dietary Chitin Particles Called Mimetic Fungi Ameliorate Colitis in Toll-Like Receptor 2/CD14- and Sex-Dependent Manners. Infect Immun 2019; 87:IAI.00006-19. [PMID: 30782858 DOI: 10.1128/iai.00006-19] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 02/05/2019] [Indexed: 02/07/2023] Open
Abstract
Chitin is a natural N-acetylglucosamine polymer and a major structural component of fungal cell walls. Dietary chitin is mucoadhesive; anti-inflammatory effects of chitin microparticles (CMPs; 1- to 10-μm diameters) have been demonstrated in models of inflammatory bowel disease (IBD). The goals of this study were to assess (i) whether CMPs among various chitin preparations are the most effective against colitis in male and female mice and (ii) whether host chitin-binding Toll-like receptor 2 (TLR2) and CD14 are required for the anti-inflammatory effect of chitin. We found that colitis in male mice was ameliorated by CMPs and large chitin beads (LCBs; 40 to 70 μm) but not by chitosan (deacetylated chitin) microparticles, oligosaccharide chitin, or glucosamine. In fact, LCBs were more effective than CMPs. In female colitis, on the other hand, CMPs and LCBs were equally and highly effective. Neither sex of TLR2-deficient mice showed anti-inflammatory effects when treated with LCBs. No anti-inflammatory effect of LCBs was seen in either CD14-deficient males or females. Furthermore, an in vitro study indicated that when LCBs and CMPs were digested with stomach acidic mammalian chitinase (AMC), their size-dependent macrophage activations were modified, at least in part, suggesting reduced particle sizes of dietary chitin in the stomach. Interestingly, stomach AMC activity was greater in males than females. Our results indicated that dietary LCBs were the most effective preparation for treating colitis in both sexes; these anti-inflammatory effects of LCBs were dependent on host TLR2 and CD14.
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