T cell immunoglobulin- and mucin-domain-containing molecule-4 attenuates concanavalin A-induced hepatitis by regulating macrophage.

Tim-4 is expressed primarily on APCs, including macrophages, and has been shown to play a critical role in T cell regulation. However, it remains unclear whether Tim-4 also plays a role in the regulation of macrophage functions. In the present study, we investigated the effects of Tim-4 on macrophage activity in Con A-induced hepatitis in mice. We found that high levels of Tim-4 expression were associated with a diminished serum level of ALT in Con A-induced hepatitis. In addition, adoptive transfer of T4-RAW cells resulted in a significant decrease in ALT levels and Con A-induced liver injuries in mice. Concurrently, T4-RAW cells transfer displayed, markedly decreased apoptosis in liver and depressed TNF-alpha secretion in serum, supporting the hypothesis that Tim-4 protects Con A-induced hepatitis by negatively regulating macrophages. Consistent with the in vivo findings, in vitro studies showed that Tim-4 overexpression in RAW264.7 cells was associated with decreased expression of CD80, CD86, and MHCII molecules and the production of TNF-alpha. Moreover, Tim-4 blockade promoted LPS-induced macrophage activation. In conclusion, these findings indicate that Tim-4 plays an important role in alleviating liver damage by inhibition of macrophage activity. Tim-4 pathway could be a potential target for the treatment of acute hepatitis.