RAGE deficiency ameliorates autoimmune hepatitis involving inhibition of IL-6 production via suppressing protein Arid5a in mice

Abstract

Abstract Activation of T cells and pro-inflammatory cytokines are essential for human autoimmune hepatitis. The receptor for advanced glycation end-product(RAGE) is one of receptors for inflammatory alarm molecule high mobility group box 1 (HMGB1), and is involved in autoimmune hepatitis. However, the molecular mechanism of RAGE in setting of autoimmune hepatitis remains elusive. This study aimed to identify the function and mechanism of RAGE in autoimmune hepatitis. The RAGE deficient mouse was used to investigate the role and underlying mechanisms by which RAGE signaling-driven immune inflammatory response in the ConA-induced experimental hepatitis. We found that the RAGE deficiency protects the mouse from liver inflammatory injury caused by ConA challenge. mRNA expression of VCAM-1, IL-6, TNF-α within the livers is markedly decreased in RAGE-deficient mice compared to wild-type mice. In parallel, RAGE deficiency leads to reduced levels of serum pro-inflammatory cytokines IL-6, TNF-α as compared to wild type control mice. RAGE-deficient mice exhibits increased of hepatic NK cells and decreased CD4+ T cells than those of wild type control mice. Notably, in vivo blockade of IL-6 in wild type mice significantly protected mice from ConA induced hepatic injury. Furthermore, RAGE deficiency impaired IL-6 production is associated with decreased expression of Arid5a in liver tissues, a half-life IL-6 mRNA regulator. RAGE signalling is important in regulating the development of autoimmune hepatitis. Immune modulation of RAGE may represent a novel therapeutic strategy to prevent immune-mediated liver injury.