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

The IL-36 family, including IL-36a, IL-36b, IL-36g, and IL-36R antagonist, belong to the IL-1 superfamily. It was reported that IL-36 plays a role in immune diseases. However, it remains unclear how IL-36 regulates inflammation. To determine the role of IL-36/IL-36R signaling pathways, we established an acute hepatitis mouse model (C57BL/6) by i.v. injection of the plant lectin Con A. We found that the levels of IL-36 were increased in the liver after Con A injection. Our results demonstrated the infiltrated neutrophils, but not the hepatocytes, were the main source of IL-36 in the liver. Using the IL-36R^2/2 mouse model (H-2^b), we surprisingly found that the absence of IL-36 signals led to aggravated liver injury, as evidenced by increased mortality, elevated serum alanine aminotransferase and aspartate aminotransferase levels, and severe liver pathological changes. 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^2/2 mice had reduced T regulatory cell numbers and chemokines in the liver. Together, our results from the mouse model suggested a vital role of IL-36 in regulating T cell function and homeostasis during liver inflammation.