title: Tim-3 promotes intestinal homeostasis in DSS colitis by inhibiting M1 polarization of macrophages.
abstract: Tim-3 is involved in the physiopathology of inflammatory bowel disease (IBD), but the underlying mechanism is unknown. Here, we demonstrated that, in mouse with DSS colitis, Tim-3 inhibited the polarization of pathogenic pro-inflammatory M1 macrophages, while Tim-3 downregulation or blockade resulted in an increased M1 response. Adoptive transfer of Tim-3-silenced macrophages worsened DSS colitis and enhanced inflammation, while Tim-3 overexpression attenuated DSS colitis by decreasing the M1 macrophage response. Co-culture of Tim-3-overexpressing macrophages with intestinal lymphocytes decreased the pro-inflammatory response. Tim-3 shaped intestinal macrophage polarization may be TLR-4 dependent since Tim-3 blockade failed to exacerbate colitis or increase M1 macrophage response in the TLR-4 KO model. Finally, Tim-3 signaling inhibited phosphorylation of IRF3, a TLR-4 downstream transcriptional factor regulating macrophage polarization. A better understanding of this pathway may shed new light on colitis pathogenesis and result in a new therapeutic strategy.
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China; State Key laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China; Beijing Institute of Transfusion Medicine, Beijing 100850, China.
authors.forename: Xingwei
authors.initials: X
authors.lastname: Jiang
authors.affiliation: Institute of Immunology, Medical School of Henan University, Kaifeng 475001, China.
authors.forename: Jiahui
authors.initials: J
authors.lastname: Yu
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Qingzhu
authors.initials: Q
authors.lastname: Shi
authors.affiliation: Department of Respiratory Diseases, First Affiliated Hospital of the Chinese PLA General Hospital, Beijing 100037, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China; Institute of Immunology, Medical School of Henan University, Kaifeng 475001, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China. Electronic address: guogangch@yahoo.com.
authors.forename: Guojiang
authors.initials: G
authors.lastname: Chen
authors.affiliation: Department of Pathology, Zhengzhou People's Hospital, YIHE Hospital, Zhengzhou 450000, China.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Renxi
authors.initials: R
authors.lastname: Wang
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: He
authors.initials: H
authors.lastname: Xiao
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Hou
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Jiannan
authors.initials: J
authors.lastname: Feng
authors.affiliation: Institute of Immunology, Medical School of Henan University, Kaifeng 475001, China.
authors.forename: Yuanfang
authors.initials: Y
authors.lastname: Ma
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Beifen
authors.initials: B
authors.lastname: Shen
authors.affiliation: State Key laboratory of Toxicology and Medical Countermeasures, Beijing 100850, China.
authors.forename: Lili
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Immunology, Beijing Institute of Basic Medical Sciences, Beijing 100850, China. Electronic address: genchenghan@163.com.
authors.forename: Gencheng
authors.initials: G
authors.lastname: Han
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D018920:Coculture Techniques; D003092:Colitis / Q000139:chemically induced / Q000276:immunology*; D003106:Colon / Q000276:immunology*; D016264:Dextran Sulfate / Q000633:toxicity; D004195:Disease Models, Animal; D055785:Gene Knockdown Techniques; D000072597:Hepatitis A Virus Cellular Receptor 2; D006706:Homeostasis; D015212:Inflammatory Bowel Diseases / Q000276:immunology*; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism; D008214:Lymphocytes / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D011991:Receptors, Virus / Q000276:immunology*; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000235:genetics
chemical_list: C442241:Havcr2 protein, mouse; D000072597:Hepatitis A Virus Cellular Receptor 2; D050838:Interferon Regulatory Factor-3; C494233:Irf3 protein, mouse; D011991:Receptors, Virus; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D016264:Dextran Sulfate
keywords: DSS colitis; Immune homeostasis; Macrophages; Tim-3