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TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling

Liu Qiang,Lei Xiaohua,Cao Zhenyu,Zhang Ju,Yan Likun,Fu Jie,Tong Qing,Qin Wei,Shao Yaoli,Liu Chun,Liu Zhiqiang,Wang Zicheng,Chu Yuan,Xu Ge,Liu Siyuan,Wen Xueyi,Yamamoto Hirofumi,Mori Masaki,Liang Xin. M.,Xu Xundi

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 of TRPM8 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 (CCl 4 ) 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 HNF4α expressions were observed in liver of CCl 4 - and BDL- treated TRPM8 −/− mice. A strong regulatory linkage between S100A9 and HNF4α 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-HNF4α signaling. M8-B might be a promising therapeutic candidate for liver fibrosis. Graphical Abstract