| First Author | Li H | Year | 2019 |
| Journal | World J Gastroenterol | Volume | 25 |
| Issue | 44 | Pages | 6527-6540 |
| PubMed ID | 31802832 | Mgi Jnum | J:290121 |
| Mgi Id | MGI:6435300 | Doi | 10.3748/wjg.v25.i44.6527 |
| Citation | Li H, et al. (2019) 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. World J Gastroenterol 25(44):6527-6540 |
| abstractText | 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. |
