Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression.
Treatment with a JAK1/2 inhibitor ameliorates murine autoimmune cholangitis induced by IFN overexpression.
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JAK1/2 抑制剂治疗可改善 IFN 过表达诱导的小鼠自身免疫性胆管炎
DOI：
10.1038/s41423-022-00904-y
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发表时间：
2022-10
影响因子：
24.1
通讯作者：
Gershwin, M. Eric
中科院分区：
文献类型：
--
作者：
Shao, Tihong;Leung, Patrick S. C.;Zhang, Weici;Tsuneyama, Koichi;Ridgway, William M.;Young, Howard A.;Shuai, Zongwen;Ansari, Aftab A.;Gershwin, M. Eric
干扰素（IFN）信号通路是主要的免疫检查点，在自身免疫发病机制中具有临床意义。我们通过改变干扰素γ代谢，构建了一个独特的名为ARE - Del的小鼠模型，该模型存在干扰素γ的慢性过表达。重要的是，这些小鼠产生了与原发性胆汁性胆管炎患者相似的免疫和临床特征，包括高滴度的自身抗体和门静脉炎症。我们假设用JAK1/2抑制剂下调干扰素信号通路会抑制胆管炎的发生和发展。为了研究这一假设，ARE - Del+/-小鼠接受JAK1/2抑制剂鲁索替尼治疗并进行系列研究。JAK抑制导致门静脉炎症和胆管损伤显著减轻，同时脾脏和肝脏的CD4+ T细胞以及CD8+ T细胞显著减少。在功能上，鲁索替尼抑制了脾脏CD4+ T细胞分泌促炎细胞因子干扰素γ和肿瘤坏死因子。此外，鲁索替尼治疗还降低了生发中心B（GC B）细胞和滤泡辅助性T（Tfh）细胞的频率，并使血清AMA水平降低。值得注意的是，鲁索替尼治疗后，肝脏和腹腔巨噬细胞急剧减少，并从M1型极化为M2型，同时IRF4表达水平升高。从机制上讲，鲁索替尼在体外抑制了巨噬细胞中白细胞介素 - 6、肿瘤坏死因子和单核细胞趋化蛋白1的分泌以及STAT1的表达，但促进了STAT6的表达，这表明M1型巨噬细胞向M2型极化是通过激活STAT6 - IRF4通路发生的。我们的数据强调了JAK/STAT信号通路在自身免疫性胆管炎中的免疫学和临床意义。
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 IFNγ metabolism. 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 IFNγ and 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.
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影响因子：
16.6
作者：
Cordell HJ;Han Y;Mells GF;Li Y;Hirschfield GM;Greene CS;Xie G;Juran BD;Zhu D;Qian DC;Floyd JA;Morley KI;Prati D;Lleo A;Cusi D;Canadian-US PBC Consortium;Italian PBC Genetics Study Group;UK-PBC Consortium;Gershwin ME;Anderson CA;Lazaridis KN;Invernizzi P;Seldin MF;Sandford RN;Amos CI;Siminovitch KA
通讯作者：
Siminovitch KA
影响因子：
12.8
作者：
Hodge DL;Berthet C;Coppola V;Kastenmüller W;Buschman MD;Schaughency PM;Shirota H;Scarzello AJ;Subleski JJ;Anver MR;Ortaldo JR;Lin F;Reynolds DA;Sanford ME;Kaldis P;Tessarollo L;Klinman DM;Young HA
通讯作者：
Young HA
影响因子：
13.5
作者：
Bae, Heekyong R.;Leung, Patrick S. C.;Tsuneyama, Koichi;Valencia, Julio C.;Hodge, Deborah L.;Kim, Seohyun;Back, Tim;Karwan, Megan;Merchant, Anand S.;Baba, Nobuyuki;Feng, Dechun;Park, Ogyi;Gao, Bin;Yang, Guo-Xiang;Gershwin, M. Eric;Young, Howard A.
通讯作者：
Young, Howard A.
DOI：
10.1084/jem.20021924
发表时间：
2003-07-21
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Lapenta C;Santini SM;Logozzi M;Spada M;Andreotti M;Di Pucchio T;Parlato S;Belardelli F
通讯作者：
Belardelli F
影响因子：
4.1
作者：
Cornez, Isabelle;Yajnanarayana, Sowmya Parampalli;Wolf, Dominik
通讯作者：
Wolf, Dominik