Hepatocytes Are Resistant to Cell Death From Canonical and Non-Canonical Inflammasome-Activated Pyroptosis

作者：Ping Sun, Jie Zhong, Hong Liao, Patricia Loughran, Joud Mulla, Guang Fu, Da Tang, Jie Fan, Timothy R. Billiar, Wentao Gao, Melanie J. Scott · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2021 · DOI：10.1016/j.jcmgh.2021.11.009 · 被引用次数：37 · 研究领域：Inflammasome and immune disorders、Liver Diseases and Immunity、Heme Oxygenase-1 and Carbon Monoxide

BACKGROUND: Pyroptosis, gasdermin-mediated programmed cell death, is readily induced in macrophages by activation of the canonical inflammasome (caspase-1) or by intracellular lipopolysaccharide (LPS)-mediated non-canonical inflammasome (caspase-11) activation. However, whether pyroptosis is induced similarly in hepatocytes is still largely controversial but highly relevant to liver pathologies such as alcoholic/nonalcoholic liver disease, drug-induced liver injury, ischemia-reperfusion and liver transplant injury, or organ damage secondary to sepsis. METHODS AND RESULTS: In this study we found that hepatocytes activate and cleave gasdermin-D (GSDMD) at low levels after treatment with LPS. Overexpression of caspase-1 or caspase-11 p10/p20 activated domains was able to induce typical GSDMD-dependent pyroptosis in hepatocytes both in vitro and in vivo. However, morphologic features of pyroptosis in macrophages (eg, pyroptotic bodies, cell flattening, loss of cell structure) did not occur in pyroptotic hepatocytes, with cell structure remaining relatively intact despite the cell membrane being breached. Our results suggest that hepatocytes activate pyroptosis pathways and cleave GSDMD, but this does not result in cell rupture and confer the same pyroptotic morphologic changes as previously reported in macrophages. This is true even with caspase-1 or caspase-11 artificial overexpression way above levels seen endogenously even after priming or in pathologic conditions. CONCLUSIONS...