The molecular mechanism of acute liver injury and inflammatory response induced by Concanavalin A

Abstract

Acute liver injury is a common but urgent clinical condition, and its underlying mechanism remains to be further elucidated. Concanavalin A (ConA)-induced liver injury was investigated in the study. Different from the caspase-dependent cell apoptosis in lipopolysaccharide/D-aminogalactose (LPS/D-GalN) induced liver injury, ConA-induced hepatocyte death was independent on caspase. Increased hepatocytic expressions of mixed lineage kinase domain like (MLKL) and receptor-interacting protein kinase 1 (RIPK1), and higher serum concentration of tumor necrosis factor-α (TNF-α) were noticed in mice with ConA-induced liver injury. Inhibition of RIPK1 protein or deletion of MLKL gene could significantly attenuate the acute liver injury and improve mice survival. Besides, the ConA treatment induced severe hepatic inflammation in wide type (WT) mice in comparison with Mlkl−/− mice, suggesting the RIPK1-MLKL-mediated hepatocellular necroptosis might participate in the process of liver injury. Moreover, mitochondrial damage associated molecular patterns (DAMPs) were subsequently released after the hepatocyte death, and further activated the p38 mitogen-activated protein kinase (MAPK) pathway, which could be reduced by deletion or inhibition of Toll-like receptor 9 (TLR9). Taken together, our research revealed that ConA-induced acute liver injury was closely related to TNF-α-mediated cell necroptosis, and inhibiting RIPK1 or deleting MLKL gene could alleviate liver injury in mice. The mitochondrial DNA released by dead hepatocytes further activated neutrophils through TLR9, thus resulting in the exacerbation of liver injury.