Physiologic expression of AhR regulates CX3CR1+ resident intestinal macrophages and promotes diabetes in NOD mice

Abstract

Abstract Susceptibility to type 1 diabetes (T1D) is influenced by both genetic and environmental factors. The environmental sensor, the aryl hydrocarbon receptor (AhR), is expressed in mucosal immune cells and can be activated by metabolites derived from the diet and microbiome. We hypothesized that these metabolites may influence the autoimmune response and subsequent susceptibility to T1D. To test this hypothesis, we generated NOD AhR knockout mice and examined the intestinal immune response and development of T1D. Female AhR knockout mice had reduced insulitis at 12 weeks of age, and a decreased incidence and onset of hyperglycemia in comparison to their wild type littermates. To determine whether physiologic expression of AhR was altering the immune response, we analyzed CD4+ T cell subsets and identified an increase in IL-10R+Foxp3+ Tregs in the lamina propria (LP) of AhR knockout mice. We also discovered a population of resident-like macrophages (CD11b+CX3CR1+) in the small intestine LP that were negatively regulated by AhR. These cells have a very strong positive correlation to LP Tregs, and correlate with protection against insulitis in NOD mice. To identify the potential source of AhR ligands that regulate these resident-like macrophages, mice were fed an AhR ligand-deficient diet. These cells were not further regulated by dietary ligands, suggesting that AhR activation originates from the intestinal microbiome. Current studies are aimed at determining how AhR regulates the expression of LP resident-like macrophages and how these cells impose their immunoregulatory functions during T1D pathogenesis.