Published online Nov 28, 2019. doi: 10.3748/wjg.v25.i44.6527
Peer-review started: September 18, 2019
First decision: October 14, 2019
Revised: October 31, 2019
Accepted: November 13, 2019
Article in press: November 13, 2019
Published online: November 28, 2019
Acute liver failure (ALF) seriously endangers human life due to its high mortality. There is currently no specific treatment method or drugs available for treating ALF. Pyroptosis is a highly inflammatory type of programmed cell death. Gasdermin D (GSDMD), as the final executor of pyroptosis, is also known as one of the important control switches in inflammatory responses. However, the actual effects of GSDMD in hepatocyte pyroptosis and ALF are still unclear.
Our findings may provide a research basis for developing inhibitors or drugs with targeted inhibition or knockdown of GSDMD for the treatment of ALF.
To detect GSDMD expression in liver tissues from humans and mice with ALF and in injured hepatocytes and to investigate the possible molecular mechanism of GSDMD-mediated hepatocyte pyroptosis for expanding inflammatory responses.
The expression levels of pyroptosis pathway proteins in liver tissues from humans with ALF, the injured AML12 cell line, and liver tissues from Galn/LPS-induced ALF mouse models were detected by using Western blot. In further study of the molecular mechanism, downregulation of GSDMD by shRNA was induced in vitro, and GSDMD knockout mice were used in a Galn/LPS-induced ALF model.
The expression of the cleaved N-terminal fragment of GSDMD protein (GSDMD-N) was increased significantly in liver tissues from humans and mice with ALF and in an in vitro injured AML12 hepatocyte cell line. The mechanism of inflammation induced by hepatocyte pyroptosis was different from the release of interleukin (IL)-1β and IL-18 by immune cell pyroptosis. Hepatocyte pyroptosis promoted and expanded inflammatory responses by upregulating monocyte chemotactic protein 1 (MCP1)/CC chemokine receptor-2 (CCR2). GSDMD knockout can significantly alleviate D-galactose/lipopolysaccharide (D-Galn/LPS)-induced ALF in mice, reduce serum inflammatory cytokines, and improve the survival rate of the ALF mice. Its effects were associated with a decrease in the expression of the MCP1/CCR2 proteins and a reduction of MCP1 release. However, the effects of downregulating GSDMD in ALF patients are still unclear and should be confirmed in clinical studies.
GSDMD-mediated hepatocyte pyroptosis plays a key role in ALF, both in humans and D-Galn/LPS-induced ALF mice. GSDMD upregulates MCP1/CCR2 to release inflammatory cytokines, which leads to deterioration of the condition in ALF. Inhibition or knockdown of GSDMD can significantly reduce the levels of inflammatory cytokines and alleviate liver injury in ALF.
The present study clarified the role of hepatocyte pyroptosis in ALF as well as its mechanism of inducing and expanding inflammatory responses by upregulating MCP1/CCR2. This study also demonstrated that targeted GSDMD inhibitors or effective intervention drugs may be a treatment approach to the prevention and treatment of ALF.