Abstract
The herpes virus entry mediator (HVEM) is an immune checkpoint molecule regulating immune response, but its role in tissue repair remains unclear. Here, we reported that HVEM deficiency aggravated hepatobiliary damage and compromised liver repair after 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-induced injury. A similar phenotype was observed in B and T lymphocyte attenuator (BTLA)-deficient mice. These were correlated with impairment of neutrophil accumulation in the liver after injury. The hepatic neutrophil accumulation was regulated by microbial-derived secondary bile acids. HVEM-deficient mice had reduced ability to deconjugate bile acids during DDC-feeding, suggesting a gut microbiota defect. Consistently, both HVEM and BTLA deficiency had dysregulated intestinal IgA responses targeting the gut microbes. These results suggest that the HVEM-BTLA signaling may restrain liver injury by regulating the gut microbiota.
Highlights
Cholestasis, i.e., impairment of bile formation and/or flow, is the most common clinical symptom shared by cholestatic liver diseases, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and secondary sclerosing cholangitis
herpes virus entry mediator (HVEM) expression in the liver was significantly increased after DDCfeeding in WT B6 mice (Supplementary Figure S1), suggesting that HVEM might involve in the pathogenesis of cholestasis
The above findings establish that the HVEM signaling, as one of the immune checkpoints, acts to restrain a chemical-induced chronic cholestatic liver injury
Summary
Cholestasis, i.e., impairment of bile formation and/or flow, is the most common clinical symptom shared by cholestatic liver diseases, such as primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and secondary sclerosing cholangitis. The accumulation of hydrophobic bile acids due to bile duct obstruction is believed to trigger hepatic inflammation and injury that eventually progress to liver fibrosis and cirrhosis, a devastating end-stage condition of many chronic liver diseases [1, 2]. There are only limited therapies, and the molecular and cellular mechanism by which cholestasis induces diseases remains incompletely understood. Both innate and adaptive immune cells are suggested to be involved in the pathophysiological process of cholestatic liver diseases. Innate immune cells such as neutrophils and macrophages can either aggravate cholestatic liver injury through producing proinflammatory cytokine and reactive oxygen species or promote liver repair by functional conversion to a reparative phenotype [3, 4]. Great progress has been made in understanding the role of the immune system during cholestasis, the relationship between immune cell reactions and cholestasis remains unclear
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