The Aryl Hydrocarbon Receptor Regulates Gut Immunity through Modulation of Innate Lymphoid Cells

Abstract

SUMMARY Innate lymphoid cells (ILCs) expressing the nuclear receptor RORγt are essential for gut immunity presumably through production of interleukin (IL)-22. The molecular mechanism underlying the development of RORγt+ ILCs is poorly understood. Here, we have shown that the aryl hydrocarbon receptor (Ahr) plays an essential role in RORγt+ ILC maintenance and function. Expression of Ahr in the hematopoietic compartment was important for accumulation of adult but not fetal intestinal RORγt+ ILCs. Without Ahr, RORγt+ ILCs had increased apoptosis and less production of IL-22. RORγt interacted with Ahr and promoted Ahr binding at the Il22 locus. Upon IL-23 stimulation, Ahr-deficient RORγt+ ILCs had reduced IL-22 expression, consistent with downregulation of IL-23R in those cells. Ahr-deficient mice succumbed to Citrobacter rodentium infection, while ectopic expression of IL-22 protected animals from early mortality. Our data uncover a previously unrecognized physiological role for Ahr in promoting innate gut immunity by regulating RORγt+ ILCs.

STAT3 Activation in Th17 and Th22 Cells Controls IL-22–Mediated Epithelial Host Defense during Infectious Colitis

“…Hence, our observations are consistent with previous studies suggesting Th17 cells to be important in the C. rodentium model (21,23). However, previous studies were often restricted in addressing the specific role of Th17 cells in vivo, as they included mice deficient in genes that are already critically important for the development or effector functions of ILC3 subsets such as IL-22, IL-23R, or AHR (5,16,21,25). In contrast, our investigations using conditional knockout mice allowed for more specific investigations into the role of Th17 and Th22 cells at the peak of infection.…”

“…Indeed, CD4 + ILC3s are crucial mediators in host defense upon infection with enteropathogenic bacteria (24). Strikingly, several features critically important during the host defense against C. rodentium such as expression of IL-17, IL-22, IL-23R, AHR, and CD4 are shared by both Th17 cells and ILC3 subsets (5,16,20,21,(24)(25)(26). Thus, studies with mice deficient in such molecules are restricted in the analysis of differential contributions by ILC3s or Th17 cells.…”

“…Thus, studies with mice deficient in such molecules are restricted in the analysis of differential contributions by ILC3s or Th17 cells. However, ILC3s act rather early upon C. rodentium infection (16,24,25), whereas major contributions of T cells occur with delayed kinetics (15,27). For the analysis of differential contributions of Th17 cells, it would be interesting to study gene-modified mice with intact ILC3 responses, but specific lack of Th17 cells.…”

Aryl hydrocarbon receptor negatively regulates NLRP3 inflammasome activity by inhibiting NLRP3 transcription

“…AhR knockout mice are hypersensitive to LPS-induced septic shock, mainly due to macrophage dysfunction 36 . AhR interacts with RORgt, promotes AhR binding at the IL-22 locus and promotes the development of RORgt þ innate lymphoid cells 37 . AhR mediates the abovementioned immunoregulatory roles mainly via regulation of various genes' expression including IL-10, IL-21, IL-22, TNF-a, IL-6 and Foxp3.…”

Functional and phenotypic heterogeneity of group 3 innate lymphoid cells

“…Vitamin A deprivation results in a loss of intestinal ILC3 in adult mice, which can be reversed upon supplementation of diet with the vitamin A‐derived metabolite retinoic acid 44, 45. Similarly, Ahr acts to sense soluble aromatic hydrocarbons – present in the diet and produced by commensal bacteria – and is essential for the development of both LTi‐like and NKp46 + ILC3, as well as IL‐22 production 14, 27, 28, 46, 47, 48, 49, 50, 51. Together these signals tune ILC3 numbers and responses and establish bidirectional interactions between ILC3 and the commensal microbiota during the initial colonization of barrier tissue sites.…”