β-arrestin2 depletion attenuates autoimmune hepatitis in mice via preventing intestinal barrier disruption and inhibiting ERS mediated intestinal epithelial cells apoptosis.

Autoimmune hepatitis (AIH) is a progressive immune-mediated inflammatory liver disease. Recent studies have highlighted the association between intestinal barrier dysfunction and chronic liver diseases, but the specific role of intestinal barrier dysfunction in AIH remains unclear and needs to be elucidated. β-arrestin2, a multifunctional scaffolding protein, has been reported to be involved in various hepatic disorders, such as acute liver injury and liver fibrosis. Nonetheless, the role of enteric β-arrestin2 in the pathogenesis of AIH is poorly understood. Here, we investigated whether intestinal barrier disruption exacerbates AIH progression, and the regulatory role of β-arrestin2. We found that dextran sulfate sodium (DSS)-induced intestinal barrier dysfunction significantly exacerbated S100-triggered hepatic injury in mice. Notably, β-arrestin2 deficiency significantly prevented intestinal barrier disruption and attenuated liver injury in AIH mice. Mechanistically, β-arrestin2 promoted the apoptosis of intestinal epithelial cells and induced barrier disruption through activating the GRP78-ATF6-CHOP signaling pathway and endoplasmic reticulum stress (ERS), while, this pro-apoptotic effect was reversed by β-arrestin2 depletion or ERS inhibitor 4-PBA. Taken together, these findings demonstrated that β-arrestin2 depletion attenuates AIH by preventing intestinal barrier function via inhibiting the ERS mediated intestinal epithelial cells apoptosis. This study indicated that β-arrestin2 as a critical regulator of gut-liver axis homeostasis in AIH, and provides an additional perspective to the development of anti-AIH therapies.