IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation
IL-36α expression is elevated in ulcerative colitis and promotes colonic inflammation
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DOI：
10.1038/mi.2015.134
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发表时间：
2016-09-01
影响因子：
8
通讯作者：
Walsh, P. T.
中科院分区：
文献类型：
--
作者：
Russell, S. E.;Horan, R. M.;Walsh, P. T.
IL-36家族细胞因子在牛皮癣发病机制中的作用已被确定。虽然银屑病和炎症性肠病（IBD）之间可能存在显著的机制重叠，但迄今为止还没有关于IL-36家族在胃肠道炎症中的研究报道。本研究表明，在溃疡性结肠炎患者的结肠黏膜中，IL-36a的表达水平特异性升高。这种升高的表达反映在小鼠炎症的结肠粘膜中，其中IL-36受体缺乏证实了这一途径是粘膜炎症的中介。在急性dss诱导的结肠炎模型中，Il36r -/-小鼠表现出疾病严重程度的降低，这与先天性炎症细胞浸润到结肠固有层的减少有关。与这些数据一致的是，肠道致病性细菌啮齿柠檬酸杆菌感染导致il36r -/-小鼠结肠内先天炎症细胞募集减少，细菌定植增加。在该模型中，IL-36R -/-小鼠也表现出T辅助细胞反应的改变，Th17反应增强，Th1反应减少，表明IL-36R信号也调节肠黏膜T细胞反应。这些数据确定了IL-36信号在结肠炎症中的新作用，并表明IL-36R途径可能代表IBD治疗干预的新靶点。
A role for the IL-36 family of cytokines has been identified in the pathogenesis of psoriasis. Although significant mechanistic overlap can exist between psoriasis and inflammatory bowel disease (IBD), to date there have been no reports investigating the IL-36 family in gastrointestinal inflammation. Here we demonstrate that expression levels of IL-36a are specifically elevated in the colonic mucosa of ulcerative colitis patients. This elevated expression is mirrored in the inflamed colonic mucosa of mice, wherein IL-36 receptor deficiency confirmed this pathway as a mediator of mucosal inflammation. Il36r -/- mice exhibited reduced disease severity in an acute DSS-induced model of colitis in association with decreased innate inflammatory cell infiltration to the colon lamina propria. Consistent with these data, infection with the enteropathogenic bacteria Citrobacter rodentium, resulted in reduced innate inflammatory cell recruitment and increased bacterial colonization in the colons of il36r -/- mice. Il36r -/- mice also exhibited altered T helper cell responses in this model, with enhanced Th17 and reduced Th1 responses, demonstrating that IL-36R signaling also regulates intestinal mucosal T-cell responses. These data identify a novel role for IL-36 signaling in colonic inflammation and indicate that the IL-36R pathway may represent a novel target for therapeutic intervention in IBD.