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

Dec 6, 2019World journal of gastroenterology

Cell death caused by Gasdermin D in liver cells increases inflammation and worsens acute liver failure by attracting immune cells through specific signals

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Abstract

The level of GSDMD-N protein in liver tissue from acute liver failure patients increased significantly (< 0.001).

Pyroptosis pathway-associated proteins were elevated in liver tissue from acute liver failure patients and hepatocyte injury models.
Downregulation of GSDMD using shRNA reduced the cell inhibition rate and decreased levels of MCP1 and its receptor CCR2 (< 0.01).
Knocking out GSDMD in a mouse model of acute liver failure significantly reduced liver inflammatory damage and improved survival (< 0.001).
GSDMD-mediated hepatocyte pyroptosis appears to recruit macrophages, contributing to increased hepatocyte death through MCP1 and CCR2 upregulation.
Inhibition of GSDMD may alleviate the pathological process associated with acute liver failure.

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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 throughandexperiments. in vitro in vivo

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). Forexperiments, 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. in vitro in vivo

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 (< 0.001)., downregulation of GSDMD by shRNA decreased the cell inhibition rate and the levels of MCP1/CCR2 proteins (< 0.01)., GSDMD knockout dramatically eliminated inflammatory damage in the liver and improved the survival of D-Galn/LPS-induced ALF mice (< 0.001). Unlike the mechanism of immune cell pyroptosis that involves releasing interleukin (IL)-1β and IL-18, GSDMD-mediated hepatocyte pyroptosis recruited macrophagesMCP1/CCR2 to aggravate hepatocyte death. However, this pathological process was inhibited after knocking down GSDMD. P In vitro P In vivo P via

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.

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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

Abstract

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