Investigation of the aryl hydrocarbon receptor’s role in colitis as it relates to observed disease-specific sex differences

Abstract

Abstract Colitis is an inflammatory bowel disease (IBD) characterized by chronic inflammation in the colon. Studies suggest that there are differences between males and females regarding colitis disease progression, severity, and response to treatment. However, there lacks clear understanding, and some inconsistencies, on what these differences are attributed to. Previously, our reports showed that activation of the aryl hydrocarbon receptor (AhR) ligand was able to reduce colitis-induced disease severity, mainly through innate lymphoid type 3 cells (ILC3), in an interleukin-22 (IL-22) dependent manner. However, noted sex differences in disease severity and treatment response were observed in the animal models of colitis. In the current study, we generated cell-specific conditional knockout (KO) mice that had AhR deficiency in Rorc-expressing immune cells (ILC3s). We induced colitis using the dextran sodium sulfate (DSS) model in wildtype (WT) control mice and conditional mouse strains with AhR deficiency in Rorc-expressing immune cells (AR mice). Weight data and serum inflammatory biomarker assays showed that male mice developed a more severe colitis compared to females, with the male AR mice even worse. In addition, while control WT DSS female mice had less severe colitis than male counterparts, AR DSS female mice had just as severe disease as males, suggesting AhR, in part, was necessary to help promote less disease severity in females. Collectively, these results show that there are sex differences in colitis induction between male and female mice, and also that these differences might in part be due to some intrinsic sex-linked expression of AhR in different cell types. The studies were supported in part by NIH grants P20GM103641.