TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling

Background: Liver fibrosis represent a major global health care burden. Data emerging from recent advances suggest TRPM8, a member of the transient receptor potential (TRP) family of ion channels, plays an essential role in various chronic inflammatory diseases. However, its role in liver fibrosis remains unknown. Herein, we assessed the potential effect ofTRPM8 in liver fibrosis. Methods: The effect of TRPM8 was evaluated using specimens obtained from classic murine models of liver fibrosis, namely wild-type (WT) and TRPM8(-/-) (KO) fibrotic mice after carbon tetrachloride (CCI4) or bile duct ligation (BDL) treatment. The role of TRPM8 was systematically evaluated using specimens obtained from the aforementioned animal models after various in vivo and in vitro experiments. Results: Clinicopathological analysis showed that TRPM8 expression was upregulated in tissue samples from cirrhosis patients and fibrotic mice. TRPM8 deficiency not only attenuated inflammation and fibrosis progression in mice but also helped to alleviate symptoms of cholangiopathies. Moreover, reduction in S100A9 and increase in HNF4 alpha expressions were observed in liver of CCl4- and BDL- treated TRPM8(-/-) mice. A strong regulatory linkage between S100A9 and HNF4 alpha was also noticed in L02 cells that underwent siRNA-mediated S100A9 knockdown and S100A9 overexpressing plasmid transfection. Lastly, the alleviative effect of a selective TRPM8 antagonist was confirmed in vivo. Conclusions: These findings suggest TRPM8 deficiency may exert protective effects against inflammation, cholangiopathies, and fibrosis through S100A9-HNF4 alpha signaling. M8-B might be a promising therapeutic candidate for liver fibrosis.

Automated summary

The study suggests that TRPM8 may have a protective effect against fibrosis by combating inflammation, cholangiopathies, and fibrosis progression through the S100A9-HNF4 alpha signaling pathway. TRPM8 deficiency in mice showed reduced inflammation and fibrosis progression, as well as alleviation of symptoms related to cholangiopathies.