Basic Study
Copyright ©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 28, 2019; 25(44): 6527-6540
Published online Nov 28, 2019. doi: 10.3748/wjg.v25.i44.6527
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
Hong Li, Xue-Ke Zhao, Yi-Ju Cheng, Quan Zhang, Jun Wu, Shuang Lu, Wei Zhang, Yang Liu, Ming-Yu Zhou, Ya Wang, Jing Yang, Ming-Liang Cheng
Hong Li, Xue-Ke Zhao, Yi-Ju Cheng, Quan Zhang, Jun Wu, Shuang Lu, Yang Liu, Ming-Yu Zhou, Ya Wang, Jing Yang, Ming-Liang Cheng, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, Guizhou Province, China
Wei Zhang, Comprehensive Liver Cancer Center of the Fifth Medical Center of PLA General Hospital, Beijing 100039, China
Author contributions: Cheng ML and Wu J designed the research; Li H, Zhao XK and Wang Y performed the experiments shown in Figures 1-5; Cheng YJ, Zhang Q, Lu S and Zhang W analyzed the data; Li H wrote the paper; Yang J, Liu Y and Zhou MY provided technical assistance and contributed to the preparation of the figures; Li H, Zhao XK and Cheng YJ contributed equally to this work. All authors reviewed the results and approved the final version of the manuscript.
Supported by the National Natural Science Foundation of China, No. 81570543 and No. 81560104.
Institutional review board statement: This study was approved by the Ethics Committee of the Affiliated Hospital of Guizhou Medical University.
Institutional animal care and use committee statement: This study was approved by the Institutional Animal Care and Use Committee of Guizhou Medical University.
Conflict-of-interest statement: The authors declare that there is no conflict of interest related to this study.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines and prepared the manuscript accordingly.
Open-Access: This is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Ming-Liang Cheng, BSc, Chief Physician, Professor, Department of Infectious Diseases, Affiliated Hospital of Guizhou Medical University, No. 28, Guiyi Road, Guiyang 550004, Guizhou Province, China.
Telephone: +86-851-86773914 Fax: +86-851-86741623
Received: September 18, 2019
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
Research background

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.

Research motivation

Our findings may provide a research basis for developing inhibitors or drugs with targeted inhibition or knockdown of GSDMD for the treatment of ALF.

Research objectives

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.

Research methods

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.

Research results

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.

Research conclusions

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.

Research perspectives

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.