Rationing AHR ligands

Signalling through the aryl hydrocarbon receptor (AHR) — which recognizes endogenous metabolites, dietary components and microbiota products — promotes the survival and function of immune cells at mucosal surfaces. Tight regulation of this signalling pathway by cytochrome P4501 (CYP1) enzymes that metabolise AHR ligands has been shown in vitro, but it was unclear whether CYP1 enzymes also regulate the mucosal immune response in vivo. Stockinger and colleagues report that experimentally inducing constitutive Cyp1a1 expression throughout the body or restricted to intestinal epithelial cells decreases AHR-dependent intestinal immune responses in mice and increases their susceptibility to enteric infection.

Credit: C. Bracey/Macmillan Publishers Limited

constitutive CYP1A1 activity decreases the availability of AHR ligands, with effects on T_H17 cells and ILC3

CD4⁺ T cells from R26^Cyp1a1 mice (which constitutively express Cyp1a1 under control of the Rosa26 promoter) were cultured under T helper 17 (T_H17) cell-inducing conditions in the presence of the endogenous AHR ligand 6-formylindolo[3,2-b]carbazole (FICZ). R26^Cyp1a1 T_H17 cells had accelerated clearance of FICZ compared with wild-type T_H17 cells and they produced less interleukin-22 (IL-22) in response to low levels of FICZ. Furthermore, R26^Cyp1a1 mice had decreased numbers of group 3 innate lymphoid cells (ILC3) in colon and small intestine. Thus, constitutive CYP1A1 activity decreases the availability of AHR ligands, with effects on T_H17 cells and ILC3. As a result, R26^Cyp1a1 mice infected with Citrobacter rodentium had increased intestinal pathology, increased bacterial dissemination and increased fatality compared with wild-type mice. In the converse experiment, mice lacking CYP1A1, CYP1A2 and CYP1B1 (Cyp1-knockout mice) failed to metabolise FICZ, had increased IL-22 production and had decreased pathology after C. rodentium infection.

Using a mouse strain that reports AHR activity through the induction of a fluorescent protein, the authors showed that Cyp1-knockout mice had increased AHR activity mainly in intestinal epithelial cells (IECs). In keeping with an important role for IECs in AHR signalling, mice in which constitutive Cyp1a1 expression was restricted to IECs (IEC^Cyp1a1 mice) had reduced numbers of intestinal ILC3, whereas mice in which Cyp1a1 expression was restricted to adaptive immune cells had normal ILC3 numbers. IEC^Cyp1a1 mice rapidly succumbed to infection with C. rodentium as a result of decreased levels of ILC3, T_H17 cells and IL-22. In bone-marrow chimaeras generated by transferring wild-type bone marrow into Cyp1-knockout recipients, the mice had increased levels of ILC3, T_H17 cells and IL-22 compared with wild-type recipients and less pathology in response to infection. This supports a crucial role for AHR ligand metabolism by non-haematopoietic cells (specifically IECs) in regulating the supply of AHR ligands to the intestinal immune system.

Further studies showed that dietary supplementation with AHR ligands could enhance immunity to C. rodentium infection in R26^Cyp1a1 mice in an IL-22-dependent manner. Therefore, the important function of CYP1 activity in maintaining intestinal immune homeostasis through regulating the availability of AHR ligands could be open to therapeutic dietary manipulation.