STAT3-Dependent Effects of Polymeric Immunoglobulin Receptor in Regulating Interleukin-17 Signaling and Preventing Autoimmune Hepatitis

Abstract

One-third of patients with autoimmune hepatitis (AIH) have cirrhosis at the time of diagnosis. The relevance of these variables, although unknown, is believed to be critical in AIH because of suspected interactions between the gut microbiome and genetic factors. Dysbiosis of the gut flora and elevated polymeric immunoglobulin receptor (pIgR) levels have been observed in both patients and mouse models. Moreover, there is a direct relationship between pIgR expression and transaminase levels in patients with AIH. In this study, we aimed to explore how pIgR influences the secretion of regenerating islet-derived 3 beta (Reg3b) and the flora composition in AIH using in vivo experiments involving patients with AIH and a concanavalin A-induced mouse model of AIH. Reg3b expression was reduced in pIgR gene (Pigr)-knockout mice compared to that in wild-type mice, leading to increased microbiota disruption. Conversely, exogenous pIgR supplementation increased Reg3b expression and maintained microbiota homeostasis. RNA sequencing revealed the participation of the interleukin (IL)-17 signaling pathway in the regulation of Reg3b through pIgR. Furthermore, the introduction of external pIgR could not restore the imbalance in gut microbiota in AIH, and the decrease in Reg3b expression was not apparent following the inhibition of signal transducer and activator of transcription 3 (STAT3). In this study, pIgR facilitated the upregulation of Reg3b via the STAT3 pathway, which plays a crucial role in preserving the balance of the intestinal microbiota in AIH. Through this research, we discovered new molecular targets that can be used for the diagnosis and treatment of AIH.

Keywords

• Autoimmune hepatitis
• Polymeric immunoglobulin receptor
• Regenerating islet-derived 3 beta
• Intestinal microbiota
• Signal transducer and activator of transcription 3