The Protective Role of IL-36/IL-36R Signal in Con A-Induced Acute Hepatitis

Abstract

Abstract The IL-36 family, including IL-36α, IL-36β, IL-36γ, and IL-36 receptor antagonist (IL-36Ra), belongs to the IL-1 super-family. Although IL-36 is known to play a role in autoimmune diseases, it remains unclear as how IL-36 regulates inflammation in the liver. To determine the role of IL-36/IL-36R signaling pathways, we established an acute hepatitis mouse model by intravenous injection of the plant lectin concanavalin A (Con A), and found that the levels of IL-36 were increased in the liver following Con A injection. We also demonstrated that intrahepatic leukocytes, but not hepatocytes, were the main source of IL-36. Moreover, further research verified that infiltrated neutrophils were the main source of IL-36γ in the liver. Using the IL-36R knockout mouse model (H-2b), surprisingly, we found that the absence of IL-36 signals led to aggravated liver injuries, as evidenced by increased mortality, accompanied by elevated serum ALT and AST levels and severe pathological changes in the liver. Further investigations demonstrated that a lack of IL-36 signaling induced intrahepatic activation of CD4+ and CD8+T lymphocytes and increased the production of inflammatory cytokines. In addition, IL-36R knockout mice had reduced Treg cell functions and chemotaxis in the liver. Together, our results suggest a vital role of IL-36 in regulating T cell function and homeostasis during liver injury and inflammation. Supported by grants from NIH (R01 EY028773, AI132674, R21 AI153586)