2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Gimap5 Expression to Ameliorate Concanavalin-Induced T Cell-Mediated Liver Injury

Abstract

Abstract GTPase of the immune-associated protein 5 (Gimap5) has been implicated in immune cell maintenance and development. A mouse model comparable to autoimmune hepatitis in humans was used to study the alterations induced in the gene expression profile of immune cells upon administration of environmental toxin 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD). In this study, we tested the hypothesis that TCDD is capable of modulating gene expression to ameliorate autoimmune hepatitis severity. Mice were injected intravenously with 12.5 mg/kg concanavalin A (ConA) and treated intraperitoneally one hour after challenge with vehicle or 10 μg/kg TCDD. TCDD-treated mice showed lower levels of liver injury enzymes, alanine aminotransferase (ALT) and aspartate aminotransferase (AST), as compared to vehicle-treated mice. Histopathological analysis revealed a reduction in liver damage in the TCDD-treated group as compared to the vehicle-treated control. Furthermore, flow cytometric analysis of liver-infiltrating mononuclear cells demonstrated that following treatment with TCDD, there was an increase in FoxP3+CD4+ Tregs as well as a decrease in proinflammatory Tbet+ Th1 and RORγt+ Th17 T helper cell subtypes after induction of the disease. Single cell RNA-sequencing was conducted on liver mononuclear cells to further assess the changes induced by TCDD. The gene expression profile showed that TCDD treatment significantly upregulated the expression of vital genes such as Gimap5, a maintenance gene for normal liver function and survival of T cells. In summary, our data suggests that TCDD is capable of inducing Gimap5 expression in autoimmune hepatitis, which in turn modulates the progression of this disease.