PMID- 31802832 OWN - NLM STAT- MEDLINE DCOM- 20200508 LR - 20210608 IS - 2219-2840 (Electronic) IS - 1007-9327 (Print) IS - 1007-9327 (Linking) VI - 25 IP - 44 DP - 2019 Nov 28 TI - Gasdermin D-mediated hepatocyte pyroptosis expands inflammatory responses that aggravate acute liver failure by upregulating monocyte chemotactic protein 1/CC chemokine receptor-2 to recruit macrophages. PG - 6527-6540 LID - 10.3748/wjg.v25.i44.6527 [doi] AB - BACKGROUND: Massive hepatocyte death is the core event in acute liver failure (ALF). Gasdermin D (GSDMD)-mediated pyroptosis is a type of highly inflammatory cell death. However, the role of hepatocyte pyroptosis and its mechanisms of expanding inflammatory responses in ALF are unclear. AIM: To investigate the role and mechanisms of GSDMD-mediated hepatocyte pyroptosis through in vitro and in vivo experiments. METHODS: The expression of pyroptosis pathway-associated proteins in liver tissues from ALF patients and a hepatocyte injury model was examined by Western blot. GSDMD short hairpin RNA (shRNA) was used to investigate the effects of downregulation of GSDMD on monocyte chemotactic protein 1 (MCP1) and its receptor CC chemokine receptor-2 (CCR2) in vitro. For in vivo experiments, we used GSDMD knockout mice to investigate the role and mechanism of GSDMD in a D-galactose/lipopolysaccharide (D-Galn/LPS)-induced ALF mouse model. RESULTS: The levels of pyroptosis pathway-associated proteins in liver tissue from ALF patients and a hepatocyte injury model increased significantly. The level of GSDMD-N protein increased most obviously (P < 0.001). In vitro, downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins (P < 0.01). In vivo, GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of D-Galn/LPS-induced ALF mice (P < 0.001). Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin (IL)-1beta and IL-18, GSDMD-mediated hepatocyte pyroptosis recruited macrophages via MCP1/CCR2 to aggravate hepatocyte death. However, this pathological process was inhibited after knocking down GSDMD. CONCLUSION: GSDMD-mediated hepatocyte pyroptosis plays an important role in the pathogenesis of ALF, recruiting macrophages to release inflammatory mediators by upregulating MCP1/CCR2 and leading to expansion of the inflammatory responses. GSDMD knockout can reduce hepatocyte death and inflammatory responses, thus alleviating ALF. CI - (c)The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved. FAU - Li, Hong AU - Li H AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Zhao, Xue-Ke AU - Zhao XK AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Cheng, Yi-Ju AU - Cheng YJ AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Zhang, Quan AU - Zhang Q AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Wu, Jun AU - Wu J AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Lu, Shuang AU - Lu S AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Zhang, Wei AU - Zhang W AD - Comprehensive Liver Cancer Center of the Fifth Medical Center of PLA General Hospital, Beijing 100039, China. FAU - Liu, Yang AU - Liu Y AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Zhou, Ming-Yu AU - Zhou MY AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Wang, Ya AU - Wang Y AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Yang, Jing AU - Yang J AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. FAU - Cheng, Ming-Liang AU - Cheng ML AD - Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China. mlcheng@yeah.net. LA - eng PT - Journal Article PL - United States TA - World J Gastroenterol JT - World journal of gastroenterology JID - 100883448 RN - 0 (CCL2 protein, human) RN - 0 (CCR2 protein, human) RN - 0 (Ccl2 protein, mouse) RN - 0 (Ccr2 protein, mouse) RN - 0 (Chemokine CCL2) RN - 0 (GSDMD protein, human) RN - 0 (Gsdmd protein, mouse) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Phosphate-Binding Proteins) RN - 0 (RNA, Small Interfering) RN - 0 (Receptors, CCR2) SB - IM MH - Animals MH - Cell Line MH - Chemokine CCL2/metabolism MH - Disease Models, Animal MH - Gene Knockdown Techniques MH - Hepatocytes/immunology/*pathology MH - Humans MH - Intracellular Signaling Peptides and Proteins/genetics/*metabolism MH - Liver Failure, Acute/chemically induced/*immunology/pathology MH - Macrophages/*immunology MH - Male MH - Mice MH - Mice, Knockout MH - Phosphate-Binding Proteins/genetics/*metabolism MH - Pyroptosis/*immunology MH - RNA, Small Interfering/metabolism MH - Receptors, CCR2/metabolism MH - Signal Transduction/immunology MH - Up-Regulation PMC - PMC6886019 OTO - NOTNLM OT - Acute liver failure OT - Gasdermin D OT - Hepatocyte OT - Monocyte chemotactic protein 1/CC chemokine receptor-2 OT - Pyroptosis COIS- Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study. EDAT- 2019/12/06 06:00 MHDA- 2020/05/10 06:00 PMCR- 2019/11/28 CRDT- 2019/12/06 06:00 PHST- 2019/09/18 00:00 [received] PHST- 2019/10/31 00:00 [revised] PHST- 2019/11/13 00:00 [accepted] PHST- 2019/12/06 06:00 [entrez] PHST- 2019/12/06 06:00 [pubmed] PHST- 2020/05/10 06:00 [medline] PHST- 2019/11/28 00:00 [pmc-release] AID - 10.3748/wjg.v25.i44.6527 [doi] PST - ppublish SO - World J Gastroenterol. 2019 Nov 28;25(44):6527-6540. doi: 10.3748/wjg.v25.i44.6527.