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

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.

Il1r2 and Tnfrsf12a in transcranial magnetic stimulation effect of ischemic stroke via bioinformatics analysis

“…[38] TNFRSF12A promotes bile acid-induced pyroptosis in cholestatic hepatocytes through NFκB/Caspase-1/ GSDMD signaling pathway, and targeting TNFRSF12A may be a promising approach for the treatment of cholestasis. [39] Table 1 A summary of miRNAs that regulate hub genes.…”

“…[38] TNFRSF12A promotes bile acid-induced pyroptosis in cholestatic hepatocytes through NFκB/Caspase-1/GSDMD signaling pathway, and targeting TNFRSF12A may be a promising approach for the treatment of cholestasis. [39] TNFRSF12A plays a key role in inflammation and cell death. [40] The activation of Tnfrsf12a can affect the inflammatory response and the activation of immune cells.…”

The Mediating Effect of 3-Methoxytyrosine on TWEAK Levels and Primary Sclerosing Cholangitis: A Genetic Perspective

“…Moreover, Tumor Necrosis Factor Receptor Superfamily Member-12A (TNFRSF12A/Fibroblast-Inducible 14, FN14) acts as the speci c binding receptor for TWEAK (Dohi et al 2012). Observational studies have noted a signi cant increase in the expression of both TWEAK and FN14 in patients with primary biliary cholangitis and obstructive cholestatic disorders (Liao et al 2023). Research con rms that bile acids can activate the Fn14-NFκB/Caspase-1/GSDMD signaling pathway, aggravating cholestatic liver injury, and TWEAK further ampli es this effect (Liao et al 2023).…”

“…Observational studies have noted a signi cant increase in the expression of both TWEAK and FN14 in patients with primary biliary cholangitis and obstructive cholestatic disorders (Liao et al 2023). Research con rms that bile acids can activate the Fn14-NFκB/Caspase-1/GSDMD signaling pathway, aggravating cholestatic liver injury, and TWEAK further ampli es this effect (Liao et al 2023). Given the pivotal role of bile acids in the onset of PSC (Liwinski et al 2020), coupled with our research ndings, we hypothesize that TWEAK may play a signi cant role in the development of PSC.…”

Integrating bulk and single‐cell data to predict the prognosis and identify the immune landscape in HNSCC

“…We identified four candidate genes using LASSO and random forest survival models that could predict overall patient survival effectively with high AUC values. Specifically, elevated TNFRSF12A expression consistently correlates with increased cellular proliferation, migration, and invasiveness 31,32 . In diverse malignancies, it orchestrates tumour growth and metastasis, aligning with the aggressive behaviour in HNSCC.…”