Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression  

作　　者：Tihong Shao Patrick S.C.Leung Weici Zhang Koichi Tsuneyama William M.Ridgway Howard A.Young Zongwen Shuai Aftab A.Ansari M.Eric Gershwi 

机构地区：[1]Department of Rheumatology and Immunology,The First Affiliated Hospital of Anhui Medical University,Hefei,China [2]Division of Rheumatology,Allergy,and Clinical Immunology,School of Medicine,University of California,Davis,CA,USA [3]Department of Pathology and Laboratory Medicine,Institute of Biomedical Sciences,Tokushima University Graduate School,Tokushima,Japan [4]Center for Cancer Research,National Cancer Institute-Frederick,Frederick,MD,USA

出　　处：《Cellular & Molecular Immunology》2022年第10期1130-1140,共11页中国免疫学杂志（英文版）

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.

摘　　要：The interferon(IFN)signaling pathways are major immunological checkpoints with clinical significance in the pathogenesis of autoimmunity.We have generated a unique murine model named ARE-Del,with chronic overexpression of IFNγ,by altering IFNγmetabolism.Importantly,these mice develop an immunologic and clinical profile similar to patients with primary biliary cholangitis,including high titers of autoantibodies and portal inflammation.We hypothesized that the downregulation of IFN signaling pathways with a JAK1/2 inhibitor would inhibit the development and progression of cholangitis.To study this hypothesis,ARE-Del^(+/−)mice were treated with the JAK1/2 inhibitor ruxolitinib and serially studied.JAK 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 cells.Functionally,ruxolitinib inhibited the secretion of the proinflammatory cytokines IFNγand TNF from splenic CD4^(+)T cells.Additionally,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 levels.Of note,liver and peritoneal macrophages were sharply decreased and polarized from M1 to M2 with a higher level of IRF4 expression after ruxolitinib treatment.Mechanistically,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 pathway.Our data highlight the significance,both immunologically and clinically,of the JAK/STAT signaling pathway in autoimmune cholangitis.

关 键 词：Primary biliary cholangitis AUTOIMMUNITY INTERFERONS Janus Kinase Inhibitors RUXOLITINIB 

分 类 号：R657.45[医药卫生—外科学]