Mindin orchestrates the macrophage-mediated resolution of liver fibrosis in mice.

Abstract

BACKGROUND & AIMS: Liver disease that progresses to cirrhosis is an enormous health problem worldwide. The extracellular matrix protein Mindin is known to have immune functions, but its role in liver homeostasis remains largely unexplored. We aimed to characterize the role of Mindin in the regulation of liver fibrosis. APPROACH & RESULTS: Mindin was upregulated in mice with carbon tetrachloride (CCl) or thioacetamide (TAA)-induced liver fibrosis, and was primarily expressed in hepatocytes. Global Mindin knockout mice were generated, which were susceptible to liver fibrosis. Notably, Mindin failed to activate hepatic stellate cells directly; however, it played a role in promoting the recruitment and phagocytosis of macrophages, and caused a phenotypic switch toward restorative macrophages during liver fibrosis. Furthermore, Mindin was found to bind to the αM-I domain of CD11b/CD18 heterodimeric receptors. To further explore this mechanism, we created Mindin and CD11b double-knockout (DKO) mice. In DKO mice, phagocytosis was further reduced, and liver fibrosis was markedly exacerbated. CONCLUSIONS: Mindin promotes the resolution of liver fibrosis and the Mindin/CD11b axis might represent a novel target for the macrophage-mediated regression of liver fibrosis.