Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression
作者机构:Department of Rheumatology and ImmunologyThe First Affiliated Hospital of Anhui Medical UniversityHefeiChina Division of RheumatologyAllergyand Clinical ImmunologySchool of MedicineUniversity of CaliforniaDavisCAUSA Department of Pathology and Laboratory MedicineInstitute of Biomedical SciencesTokushima University Graduate SchoolTokushimaJapan Center for Cancer ResearchNational Cancer Institute-FrederickFrederickMDUSA
出 版 物:《Cellular & Molecular Immunology》 (中国免疫学杂志(英文版))
年 卷 期:2022年第19卷第10期
页 面:1130-1140页
核心收录:
学科分类:1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100210[医学-外科学(含:普外、骨外、泌尿外、胸心外、神外、整形、烧伤、野战外)] 10[医学]
基 金:This work is supported in part by the National Institutes of Health grant DK123262(MEG) federal funds directly from the intramural research programs of the NCI,CCR,Laboratory of Cancer Immunometabolism under Contract No.HHSN261200800001E(HAY) TS’s fellowship is supported in part by an award(#81871296)from the National Natural Science Foundation of China
主 题:Primary biliary cholangitis Autoimmunity Interferons Janus Kinase Inhibitors Ruxolitinib
摘 要:The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of *** have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγ***,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal *** hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of *** study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially *** inhibition resulted in a significant reduction in portal inflammation and bile duct damage,associated with a significant reduction in splenic and hepatic CD4^(+)T cells and CD8^(+)T ***,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic CD4^(+)T ***,ruxolitinib treatment also decreased the frequencies of germinal center B(GC B)cells and T follicular helper(Tfh)cells and led to lower serological AMA *** note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib ***,ruxolitinib inhibited the secretion of IL-6,TNF and MCP1 and the expression of STAT1 but promoted the expression of STAT6 in macrophages in vitro,indicating that M1 macrophage polarization to M2 occurred through activation of the STAT6-IRF4 *** data highlight the significance,both immunologically and clinically,of the JAK/STAT signaling pathway in autoimmune cholangitis.