坏死性下垂
促炎细胞因子
生物
炎症
坏死
肿瘤坏死因子α
自身免疫性肝炎
细胞因子
肝炎
免疫学
程序性细胞死亡
癌症研究
细胞生物学
细胞凋亡
遗传学
作者
Claudia Günther,Gui-Wei He,Andreas E. Kremer,James M. Murphy,Emma J. Petrie,Kerstin Amann,Peter Vandenabeele,Andreas Linkermann,Christopher Poremba,Ulrike Schleicher,Christin Dewitz,Stefan Krautwald,Markus F. Neurath,Christoph Becker,Stefan Wirtz
摘要
Although necrosis and necroinflammation are central features of many liver diseases, the role of programmed necrosis in the context of inflammation-dependent hepatocellular death remains to be fully determined. Here, we have demonstrated that the pseudokinase mixed lineage kinase domain–like protein (MLKL), which plays a key role in the execution of receptor-interacting protein (RIP) kinase–dependent necroptosis, is upregulated and activated in human autoimmune hepatitis and in a murine model of inflammation-dependent hepatitis. Using genetic and pharmacologic approaches, we determined that hepatocellular necrosis in experimental hepatitis is driven by an MLKL-dependent pathway that occurs independently of RIPK3. Moreover, we have provided evidence that the cytotoxic activity of the proinflammatory cytokine IFN-γ in hepatic inflammation is strongly connected to induction of MLKL expression via activation of the transcription factor STAT1. In summary, our results reveal a pathway for MLKL-dependent programmed necrosis that is executed in the absence of RIPK3 and potentially drives the pathogenesis of severe liver diseases.
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