Interactions Between Aryl Hydrocarbon Receptor and the Microbiome Regulate Intestinal Macrophages in Non Obese Diabetic Mice

Abstract

Abstract Type 1 diabetes (T1D) arises from a complex interaction between genetic and environmental factors. Multiple environmental signals predicted to impact T1D development occur at the intestinal surface, as a result of exposures through ingestion, dietary antigens, and microbial colonization. It is hypothesized that an inappropriate immune response to these exposures precipitates overt T1D. We discovered a novel mechanism by which environmental surveillance interacts with the immune system: immunosuppressive lamina propria (LP) macrophage regulation via the aryl hydrocarbon receptor (AhR). In NOD mice, AhR negatively regulates a macrophage subset (CD11b+CX3CR1+MHCIIhi; AhR-MFs) that have a strong positive correlation CD4+IL10R+Foxp3+ Tregs in the small intestine. 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 ligands produced by the intestinal microbiome. Therefore, germ-free NOD AhR knockout mice were derived and the AhR-MF population was measured. In the absence of the microbiome, both AhR knockout and wild type mice had high levels of AhR-MFs, demonstrating that the microbiome is required for AhR-mediated regulation of LP macrophages. RNAseq analysis of sorted AhR-MFs demonstrate that these cells are antigen presenting but lack an inflammatory gene signature. Currently, single cell sequencing of CD45+ LP cells from AhR knockout NOD mice is being performed to identify how AhR alters macrophage differentiation and predict mechanisms of crosstalk with intestinal CD4+ T cell populations. Supported by R00 DK117509-03, T32 ES007059