Cross-regulation by TLR4 and T cell Ig mucin-3 determines severity of liver injury in a CCl4-induced mouse model

Acute liver injury is a common pathological basis for a variety of acute liver diseases in the clinic, which can eventually lead to liver fibrosis and even liver failure. In this study, we found that T cell Ig and mucin domain protein 3 (Tim-3) and TLR4 receptors play important roles in CCl4-induced acute liver injury. Tim-3 is a negative regulator that is expressed by T cells and macrophages. Using antibodies against Tim-3 (anti-Tim-3 Ab), we studied the Tim-3 signal in an animal model of acute liver injury and found that a large number of inflammatory factors were upregulated. In vitro experimental data shown that anti-Tim-3 Ab treatment increased interferon-ɣ production by concanavalin A (ConA)-stimulated spleen T cells, and we found that the expression level of interleukin (IL)-6 was increased in a macrophage/spleen T cell coculture system, while administration of galectin-9 (Gal-9, a Tim-3 ligand) reduced the IL-6 production. This indicates the importance of the Tim-3/Gal-9 signalling pathway in maintaining hepatic homeostasis. The Tim-3 signalling pathway inhibits TLR4-mediated NF-κB activity, and an anti-Tim-3 Ab does not affect the liver injury in TLR4-deficient mice. Regulation between Tim-3 and TLR4 determines the severity of liver damage. The negative regulation of Tim-3 reflects the protective mechanisms of patients with impaired liver function, and these results provide important information about innate and adaptive responses in the regulation of liver damage. This finding is potentially important for the study of early liver injury.