Aryl hydrocarbon receptor mediates the maintenance and immune regulatory functions of gut-resident macrophages

Gut macrophages play critical roles in sensing the luminal environment and orchestrating the gut immune system. The aryl hydrocarbon receptor (AhR) is an environmental sensor that responds to xenobiotic aromatic hydrocarbons and endogenous indole derivatives. To investigate the role of AhR in macrophages within the small intestinal lamina propria, we employed an AhR deletion system using the CX₃CR1 promoter-driven Cre recombinase. Bone marrow-derived macrophages lacking AhR exhibited normal differentiation and phagocytic capabilities but reduced IL-10 production. In the gut, AhR deficiency led to a reduction in the number of tissue-resident macrophages expressing Tim4 and CD4, whereas populations of F4/80⁺ and CD11c⁺ cells remained unaffected. Interestingly, AhR deficiency in CX₃CR1⁺ macrophages increased the population of CD103⁺CD11b⁺ dendritic cells in the lamina propria. The role of AhR in gut macrophages was examined using indomethacin-induced enteropathy and Salmonella infection models. AhR deficiency exacerbated indomethacin-induced enteropathy, which is characterized by enhanced monocyte infiltration. AhR-deficient gut macrophages demonstrated improved host defense against Salmonella infection through enhanced phagocytosis and reactive oxygen species production. These findings highlight that AhR signaling regulates the maintenance and function of gut tissue-resident macrophages, contributing to immune homeostasis within the gut microenvironment.