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

被引：22

作者：

Liao, Min ^{[1
,2
,3
,4
]}

Liao, Junwei ^{[3
,4
,5
]}

Qu, Jiaquan ^{[1
,2
,3
,4
,6
]}

Shi, Pan ^{[1
,2
,3
,4
]}

Cheng, Ying ^{[1
,2
,3
,4
]}

Pan, Qiong ^{[1
,2
,3
,4
]}

Zhao, Nan ^{[1
,2
,3
,4
]}

Zhang, Xiaoxun ^{[1
,2
,3
,4
]}

Zhang, Liangjun ^{[1
,2
,3
,4
]}

Tan, Ya ^{[1
,2
,3
,4
]}

Li, Qiao ^{[1
,2
,3
,4
]}

Zhu, Jin-Fei ^{[1
,7
]}

Li, Jianwei ^{[8
]}

Zhang, Chengcheng ^{[8
]}

Cai, Shi-Ying ^{[9
,10
]}

Chai, Jin ^{[1
,2
,3
,4
]}

机构：

[1] Third Mil Med Univ, Army Med Univ, Affiliated Hosp 1, Southwest Hosp,Dept Gastroenterol, Chongqing 400038, Peoples R China

[2] Third Mil Med Univ, Army Med Univ, Affiliated Hosp 1, Southwest Hosp,Inst Digest Dis PLA, Chongqing 400038, Peoples R China

[3] Third Mil Med Univ, Army Med Univ, Cholestat Liver Dis Ctr, Southwest Hosp,Affiliated Hosp 1, Chongqing 400038, Peoples R China

[4] Third Mil Med Univ, Affiliated Hosp 1, Southwest Hosp,Army Med Univ, Ctr Metab Associated Fatty Liver Dis, Chongqing 400038, Peoples R China

[5] Cent South Univ, Sch Sci, Changsha 410083, Hunan, Peoples R China

[6] Med Coll Jishou Univ, Dept Med Imaging Technol, Jishou 416000, Hunan, Peoples R China

[7] Nanchang Univ, Queen Mary Sch, Nanchang 330031, Jiangxi, Peoples R China

[8] Third Mil Med Univ, Southwest Hosp, Inst Hepatobiliary Surg, Chongqing 400038, Peoples R China

[9] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06520 USA

[10] Yale Univ, Liver Ctr, Sch Med, New Haven, CT 06520 USA

来源：

CELL DEATH DISCOVERY | 2023年 / 9卷 / 01期

基金：

中国国家自然科学基金; 国家自然科学基金重大研究计划;

关键词：

MULTIFUNCTIONAL CYTOKINE; TWEAK/FN14; PATHWAY; TNF SUPERFAMILY; ACTIVATION; EXPRESSION;

D O I：

10.1038/s41420-023-01326-z

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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 NF kappa B/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 NF kappa B/Caspase-1/GSDMD signaling and thereby ameliorates cholestatic liver injury. As such, targeting TNFRSF12A could be a promising approach to treating cholestasis.

引用

页数：10

共 32 条

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