Targeting cIAPs attenuates CCl4-induced liver fibrosis by increasing MMP9 expression derived from neutrophils.

Abstract

AIMS:

Liver fibrosis is a growing public health concern without effective medical treatment. Recent reports have indicated that inhibitors of apoptosis proteins (IAPs) were potential targets for idiopathic pulmonary fibrosis therapy. However, their roles have not been well identified in liver fibrosis.

METHODS:

The expression of IAPs were examined in human liver tissue and experimental mouse models. Liver fibrosis in CCl4-induced mouse models were investigated by Sirius red staining, RT-PCR, Western blotting after hepatocytes-specific cIAP2 knockout or IAPs inhibitor APG-1387 treatment. The underlying molecular mechanism of APG-1387 action was explored by apoptosis analysis, matrix metalloprotein 9 (MMP9) inhibition, neutrophils depletion, and CC Motif Chemokine Ligand 5 (CCL5) gene knockout in vitro and in vivo.

FINDINGS:

Our study showed that increased expression of cIAP2 was associated with liver fibrosis severity in liver tissues. Deletion of cIAP2 from hepatocytes or degrading cIAPs by APG-1387 ameliorated liver fibrosis induced by CCl4. APG-1387 treatment exhibited increased expression of MMP9 and resulted in higher ratio of MMP9 to tissue inhibitor of metalloproteinase-1. MMP9 was mainly derived from CCL5 chemotactic neutrophils. Further, MMP9 inhibition by CTT peptide, neutrophil depletion by Ly6G antibody or CCL5 deficiency blocked the anti-fibrotic effects of APG-1387 in vivo.

SIGNIFICANCE:

These results suggested that cIAPs, especially cIAP2, might play a novel role in the pathogenesis of liver fibrosis, and targeting cIAPs represented a promising therapeutic strategy for liver fibrosis by increasing MMP9 expression induced by CCL5 chemotactic neutrophils.

• Authors: Yi Wu, Suwen Lu, Xuan Huang, Yuanyuan Liu, Kuiyuan Huang, Ziying Liu, Weikang Xu, Wei Zhu, Jinlin Hou, Hongyan Liu, Xiaoyong Zhang
• Journal: Life sciences (Life Sci) Vol. 289 Pg. 120235 (Jan 15 2022) ISSN: 1879-0631 [Electronic] Netherlands
• PMID: 34914932 (Publication Type: Journal Article)
• Copyright: Copyright © 2021. Published by Elsevier Inc.

Chemical References

• BIRC3 protein, human
• Baculoviral IAP Repeat-Containing 3 Protein
• MMP9 protein, human
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Baculoviral IAP Repeat-Containing 3 Protein (genetics, metabolism)
• Carbon Tetrachloride Poisoning (genetics, metabolism, pathology)
• Gene Deletion
• Gene Expression Regulation, Enzymologic
• Humans
• Liver Cirrhosis (genetics, metabolism, pathology)
• Male
• Matrix Metalloproteinase 9 (biosynthesis, genetics)
• Mice
• Mice, Knockout
• Neutrophils (metabolism, pathology)