TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling

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

doi:10.1186/s13578-022-00789-4

TRPM8 deficiency attenuates liver fibrosis through S100A9-HNF4α signaling

Cell Biosci. 2022 May 7;12(1):58. doi: 10.1186/s13578-022-00789-4.

Authors

Qiang Liu^{1

2}, Xiaohua Lei¹, Zhenyu Cao¹, Ju Zhang¹, Likun Yan¹, Jie Fu¹, Qing Tong¹, Wei Qin¹, Yaoli Shao¹, Chun Liu¹, Zhiqiang Liu¹, Zicheng Wang¹, Yuan Chu¹, Ge Xu¹, Siyuan Liu¹, Xueyi Wen¹, Hirofumi Yamamoto³, Masaki Mori⁴, Xin M Liang⁵, Xundi Xu^{6

7}

Affiliations

¹ Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, 139 Renminzhong Road, Changsha, 410011, People's Republic of China.
² Hunan Cancer Hospital, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, 410013, People's Republic of China.
³ Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Suita City, Osaka, 565-0871, Japan.
⁴ Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan.
⁵ Wellman Center for Photomedicine, Division of Hematology and Oncology, Division of Endocrinology, Massachusetts General Hospital, VA Boston Healthcare System, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02115, USA. xin.m.liang.phd@gmail.com.
⁶ Hunan Provincial Key Laboratory of Hepatobiliary Disease Research, Division of Hepato-Biliary-Pancreatic Surgery, Department of Surgery, The Second Xiangya Hospital, Central South University, 139 Renminzhong Road, Changsha, 410011, People's Republic of China. xuxundi@csu.edu.cn.
⁷ Department of General Surgery, Health Science Center, South China Hospital, Shenzhen University, No.1, Fuxin Road, Pinghu Street, Longgang District, Shenzhen, 518116, People's Republic of China. xuxundi@csu.edu.cn.

Abstract

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 (CCl₄) 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 CCl₄- 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.

Keywords: ECM; HNF4α; Inflammation; Liver fibrosis; S100A9; TRPM8.

Abstract

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