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研究揭示FADD和Caspase-8调节肠道稳态和炎症的机制
作者:小柯机器人 发布时间:2020/5/2 13:31:13

近日,德国科隆大学Manolis Pasparakis研究团队发现,FADD和Caspase-8通过控制MLKL和GSDMD介导的肠上皮细胞死亡来调节肠道稳态和炎症。该项研究成果于2020年5月1日在线发表在《免疫》杂志上。

研究人员发现,caspase-8及其辅助蛋白FADD在肠道上皮细胞(IEC)中起作用,从而调节Z-DNA结合蛋白1(ZBP1)和肿瘤坏死因子受体1(TNFR1)介导的受体相互作用蛋白激酶1(RIPK1)下游的肠道炎症和RIPK3信号。
 
IEC特异性FADD或caspase-8缺失的小鼠发展为结肠炎,并依赖于混合谱系激酶样(MLKL)蛋白介导的上皮细胞坏死。但是,MLKL缺失可完全预防由上皮caspase-8敲除引起的回肠炎,但对于IEC中缺失FADD的小鼠,回肠炎仅能部分缓解。
 
这些遗传研究表明,在上皮FADD缺失的小鼠中,MLKL非依赖性回肠炎的发生需要caspase-8和gasdermin-D(GSDMD)。因此,FADD通过抑制MLKL诱导的焦亡和caspase-8-GSDMD依赖性上皮细胞凋亡样死亡而阻止ZBP1和TNFR1下游的肠道炎症。
 
据介绍,控制肠道上皮细胞(IEC)死亡的途径可调节肠道免疫稳态,并有助于炎症性肠病的发病。
 
附:英文原文

Title: FADD and Caspase-8 Regulate Gut Homeostasis and Inflammation by Controlling MLKL- and GSDMD-Mediated Death of Intestinal Epithelial Cells

Author: Robin Schwarzer, Huipeng Jiao, Laurens Wachsmuth, Achim Tresch, Manolis Pasparakis

Issue&Volume: 2020-05-01

Abstract: Pathways controlling intestinal epithelial cell (IEC) death regulate gut immune homeostasisand contribute to the pathogenesis of inflammatory bowel diseases. Here, we show thatcaspase-8 and its adapter FADD act in IECs to regulate intestinal inflammation downstreamof Z-DNA binding protein 1 (ZBP1)- and tumor necrosis factor receptor-1 (TNFR1)-mediatedreceptor interacting protein kinase 1 (RIPK1) and RIPK3 signaling. Mice with IEC-specificFADD or caspase-8 deficiency developed colitis dependent on mixed lineage kinase-like(MLKL)-mediated epithelial cell necroptosis. However, MLKL deficiency fully preventedileitis caused by epithelial caspase-8 ablation, but only partially ameliorated ileitisin mice lacking FADD in IECs. Our genetic studies revealed that caspase-8 and gasdermin-D(GSDMD) were both required for the development of MLKL-independent ileitis in micewith epithelial FADD deficiency. Therefore, FADD prevents intestinal inflammationdownstream of ZBP1 and TNFR1 by inhibiting both MLKL-induced necroptosis and caspase-8-GSDMD-dependentpyroptosis-like death of epithelial cells.

DOI: 10.1016/j.immuni.2020.04.002

Source: https://www.cell.com/immunity/fulltext/S1074-7613(20)30160-6

期刊信息

Immunity:《免疫》,创刊于1994年。隶属于细胞出版社,最新if:21.522
官方网址:https://www.cell.com/immunity/home
投稿链接:https://www.editorialmanager.com/immunity/default.aspx