研究揭示FADD和Caspase-8調節腸道穩態和炎症的機制

研究揭示FADD和Caspase-8調節腸道穩態和炎症的機制

作者：

小柯機器人

發布時間：2020/5/2 13:31:13

近日，德國科隆大學Manolis Pasparakis研究團隊發現，FADD和Caspase-8通過控制MLKL和GSDMD介導的腸上皮細胞死亡來調節腸道穩態和炎症。該項研究成果於2020年5月1日在線發表在《免疫》雜誌上。

研究人員發現，caspase-8及其輔助蛋白FADD在腸道上皮細胞（IEC）中起作用，從而調節Z-DNA結合蛋白1（ZBP1）和腫瘤壞死因子受體1（TNFR1）介導的受體相互作用蛋白激酶1（RIPK1）下遊的腸道炎症和RIPK3信號。

 

IEC特異性FADD或caspase-8缺失的小鼠發展為結腸炎，並依賴於混合譜系激酶樣（MLKL）蛋白介導的上皮細胞壞死。但是，MLKL缺失可完全預防由上皮caspase-8敲除引起的迴腸炎，但對於IEC中缺失FADD的小鼠，迴腸炎僅能部分緩解。

 

這些遺傳研究表明，在上皮FADD缺失的小鼠中，MLKL非依賴性迴腸炎的發生需要caspase-8和gasdermin-D（GSDMD）。因此，FADD通過抑制MLKL誘導的焦亡和caspase-8-GSDMD依賴性上皮細胞凋亡樣死亡而阻止ZBP1和TNFR1下遊的腸道炎症。

 

據介紹，控制腸道上皮細胞（IEC）死亡的途徑可調節腸道免疫穩態，並有助於炎症性腸病的發病。

 

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