sTim-3 alleviates liver injury via regulation of the immunity microenvironment and autophagy

Abstract

AbstractLiver failure (LF) is a monocyte/macrophage-mediated liver injury that has been associated with inflammatory mediators. However, the mechanism through which monocytes/macrophages regulate LF has not been fully elucidated. In this study, we investigated the role of soluble T-cell immunoglobulin domain and mucin domain-containing molecule-3 (sTim-3) in inhibition of release of inflammatory mediators. We further assess this role in protection against D-galactosamine (D-GalN)/lipopolysaccharide (LPS)-induced acute liver failure (ALF), via monocyte/macrophage regulation and autophagy induction in mice. Our findings indicate significantly higher plasma sTim-3 in acute-on-chronic liver failure (ACLF) group relative to other groups, with this trend associated with disease progression. Furthermore, infiltrated recombinant sTim-3 inhibited release of various inflammatory mediators, including cytokines and human high-mobility group box-1 (HMGB1), potentially via autophagy induction. Furthermore, H&E staining and the low levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in ALF mice, supported that recombinant sTim-3 effectively alleviated liver injury. Moreover, sTim-3 induced changes in monocyte/macrophage population in mice’s liver or blood, which consequently caused a reduction in proinflammatory CD11bhiF4/80lo monocyte-derived macrophages and Ly-6C(+)CD11b(+) monocytes. Conversely, sTim-3 increased autophagy levels of hepatic CD11b(+) monocyte-derived macrophages and decreased apoptosis rate of CD11b (+) monocytes in the blood. Collectively, our findings demonstrated that sTim-3 alleviated inflammatory response and liver injury by promoting autophagy and regulating monocyte/macrophage function. This indicates its potential for future development of novel therapeutic strategies against LF.