Glycine attenuates double-stranded RNA-induced autoimmune cholangitis and pancreatitis by modulating innate immune signaling in mice.

Autoimmunity plays a central role in hepatobiliary and pancreatic diseases; however, the mechanisms underlying the initiation and progression of autoimmune cholangitis and pancreatitis remain incompletely understood. Glycine, a nutritionally nonessential amino acid, has immunomodulatory and hepatoprotective properties. This study investigated the effects of dietary glycine on innate and adaptive immune responses induced by double-stranded RNA. Chronic administration of polyinosinic-polycytidylic acid for 24 weeks induced cholangitis- and pancreatitis-like phenotypes, characterized by elevated serum alkaline phosphatase and amylase levels, increased levels of autoantibodies, including antimitochondrial M2 and anti-lactoferrin antibodies, and periductal infiltration of macrophages, T cells, and B cells. These changes were accompanied by the induction of proinflammatory cytokines and type I interferons. Dietary glycine supplementation significantly attenuated these pathological features in both preventive and therapeutic settings. Glycine suppressed early innate immune activation, as evidenced by reduced hepatic expression of tumor necrosis factor α, interleukin (IL)-1β, IL-6, IL-12b, and type I interferons. Furthermore, glycine modulated downstream adaptive immune responses, including suppression of T helper (Th)2-related cytokines (IL-4 and IL-13), the Th17-related cytokine IL-23a, and the regulatory cytokine IL-10, along with reduced autoantibody production. These findings suggest that glycine acts upstream in the inflammatory cascade by attenuating innate immune signaling that drives downstream adaptive immune responses. In conclusion, dietary glycine suppresses double-stranded RNA-induced innate and autoimmune responses in the liver and pancreas, supporting its potential as a safe, mechanism-based therapeutic strategy for autoimmune hepatobiliary and pancreatic diseases. SIGNIFICANCE STATEMENT: Dietary glycine suppresses double-stranded RNA-triggered innate immune activation and autoantibody production, preventing autoimmune-like cholangitis and pancreatitis. By modulating upstream toll-like receptor 3/pattern-recognition receptor and type I interferon pathways, glycine provides broad yet pharmacologically safe immunoregulation with potential relevance to autoimmune hepatobiliary and pancreatic diseases such as primary biliary cholangitis and autoimmune pancreatitis.