Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis

Min Liao; Junwei Liao; Jiaquan Qu; Pan Shi; Ying Cheng; Qiong Pan; Nan Zhao; Xiaoxun Zhang; Liangjun Zhang; Ya Tan; Qiao Li; Jin-Fei Zhu; Jianwei Li; Chengcheng Zhang; Shi-Ying Cai; Jin Chai

doi:10.1038/s41420-023-01326-z

Hepatic TNFRSF12A promotes bile acid-induced hepatocyte pyroptosis through NFκB/Caspase-1/GSDMD signaling in cholestasis

Cell Death Discov. 2023 Jan 23;9(1):26. doi: 10.1038/s41420-023-01326-z.

Authors

Min Liao^#^{1

2

3}, Junwei Liao^#^{3

4}, Jiaquan Qu^#^{1

2

3

5}, Pan Shi^#^{1

2

3}, Ying Cheng^{1

2

3}, Qiong Pan^{1

2

3}, Nan Zhao^{1

2

3}, Xiaoxun Zhang^{1

2

3}, Liangjun Zhang^{1

2

3}, Ya Tan^{1

2

3}, Qiao Li^{1

2

3}, Jin-Fei Zhu^{1

6}, Jianwei Li⁷, Chengcheng Zhang⁷, Shi-Ying Cai⁸, Jin Chai^{9

10

11}

Affiliations

¹ Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China.
² Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China.
³ Cholestatic Liver Diseases Center and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China.
⁴ Central South University School of Sciences, Changsha, Hunan, 410083, China.
⁵ Department of Medical Imaging Technology, Medical College of Jishou University, Jishou, Hunan, 416000, China.
⁶ Queen Mary School, Nanchang University, Nanchang, Jiangxi, 330031, China.
⁷ Institute of Hepatobiliary Surgery, Southwest Hospital, Third Military Medical University, Chongqing, 400038, China.
⁸ Department of Internal Medicine and Liver Center, Yale University School of Medicine, New Haven, CT, 06520, USA.
⁹ Department of Gastroenterology, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. jin.chai@cldcsw.org.
¹⁰ Institute of Digestive Diseases of PLA, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. jin.chai@cldcsw.org.
¹¹ Cholestatic Liver Diseases Center and Center for Metabolic-Associated Fatty Liver Diseases, The First Affiliated Hospital (Southwest Hospital), Third Military Medical University (Army Medical University), Chongqing, 400038, China. jin.chai@cldcsw.org.

^# Contributed equally.

Abstract

Tumor necrosis factor receptor superfamily member-12A (TNFRSF12A) plays a critical role in inflammation and cell death. It is expressed in multiple tissues yet extremely low in normal liver. To date, little is known about its role in cholestasis. Therefore, we sought to delineate the role of TNFRSF12A in cholestasis and its underlying mechanisms. Human liver tissues were collected from patients with obstructive cholestasis (OC) or primary biliary cholangitis (PBC). Tnfrsf12a knockout (KO) mice were generated. Cholestasis was induced by bile-duct ligation (BDL) or 0.1% 5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-feeding. Human hepatoma PLC/PRF/5-ASBT and THP1 cell lines or primary mouse hepatocytes were used for mechanistic studies. Hepatic TNFRSF12A expression was markedly increased in OC or PBC patients. Genetic ablation of Tnfrsf12a in BDL- and 0.1%DDC-induced cholestatic mice significantly attenuated cholestatic liver injury with remarkable reduction of hepatocyte pyroptosis but without changing scores of necroptosis and apoptosis. Morphological features of hepatocyte pyroptosis and increased levels of pyroptosis-related proteins, NLRP3, cleaved-Caspase-1, and cleaved-GSDMD in OC patients and BDL-mice confirmed this observation. Further mechanistic studies revealed that bile acids (BAs) induced TNFRSF12A expression by enhancing the transcription factor c-JUN binding to the TNFRSF12A promoter and subsequently initiated hepatocyte pyroptosis by the NFκB/Caspase-1/GSDMD signaling. Interestingly, TWEAK, a typical ligand of TNFRSF12A, secreted by infiltrated macrophages in cholestatic livers, enhanced TNFRSF12A-induced hepatocyte pyroptosis. Taken together, we report, for the first time, that hepatic TNFRSF12A is dramatically increased in human cholestasis. Deletion of TNFRSF12A inhibits BAs-induced hepatocyte pyroptosis through the NFκB/Caspase-1/GSDMD signaling and thereby ameliorates cholestatic liver injury. As such, targeting TNFRSF12A could be a promising approach to treating cholestasis.