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

Abstract

Activation of T cells and pro-inflammatory cytokines are essential for human autoimmune hepatitis. RAGE is one of the receptors for the inflammatory alarm molecule high mobility group box 1 (HMGB1), and it is involved in autoimmune hepatitis. However, the molecular mechanism of RAGE in the context of autoimmune hepatitis remains elusive. This study aimed to identify the function and mechanism of RAGE in autoimmune hepatitis. The role and underlying mechanisms of RAGE signaling-driven immune inflammatory response in ConA-induced experimental hepatitis were examined using the RAGE-deficient mice. We found that the RAGE deficiency protected the mouse from liver inflammatory injury caused by the ConA challenge. mRNA expression of VCAM-1, IL-6, and 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 the serum pro-inflammatory cytokines IL-6 and TNF-α as compared with wild-type control mice. RAGE-deficient mice exhibit increased hepatic NK cells and decreased CD4+ T cells compared with 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 and was associated with decreased expression of Arid5a in liver tissues, a half-life IL-6 mRNA regulator. RAGE signaling is important in regulating the development of autoimmune hepatitis. Immune regulation of RAGE may represent a novel therapeutic strategy to prevent immune-mediated liver injury.