AHR in the intestinal microenvironment: safeguarding barrier function

Abstract

Mammalian aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor that belongs to the basic helix-loop-helix (bHLH)-PAS family of transcription factors, which are evolutionarily conserved environmental sensors. In the absence of ligands, AHR resides in the cytoplasm in a complex with molecular chaperones such as HSP90, XAP2 and p23. Upon ligand binding, AHR translocates into the nuclear compartment, where it dimerizes with its partner protein, AHR nuclear translocator (ARNT), an obligatory partner for the DNA-binding and functional activity. Historically, AHR had mostly been considered as a key intermediary for the detrimental effects of environmental pollutants on the body. However, following the discovery of AHR-mediated functions in various immune cells, as well as the emergence of non-toxic 'natural' AHR ligands, this view slowly began to change, and the study of AHR-deficient mice revealed a plethora of important beneficial functions linked to AHR activation. This Review focuses on regulation of the AHR pathway and the barrier-protective roles AHR has in haematopoietic, as well as non-haematopoietic, cells within the intestinal microenvironment. It covers the nature of AHR ligands and feedback regulation of the AHR pathway, outlining the currently known physiological functions in immune, epithelial, endothelial and neuronal cells of the intestine.

Fig. 1. Mechanisms for negative-feedback regulation of AHR activity.

a | Cytochrome P450 family 1 (CYP1)-catalysed degradation of aryl hydrocarbon receptor (AHR)-activating ligand. b | Repression of AHR transactivation by AHR repressor (AHRR). c | Induced degradation of AHR through 2,3,7,8-tetrachlorodibenzo-p-dioxin poly(ADP-ribose) polymerase (TIPARP)-mediated ribosylation. AHRE, AHR response element (DNA-binding site for AHR).

Fig. 2. AHR in the intestinal microenvironment.

a | Under homeostatic conditions, ligand-dependent aryl hydrocarbon receptor (AHR) signalling via dietary or microbiota-derived ligands in various immune and non-haematopoietic cells is critical for the preservation of intestinal barrier integrity and function via secretion of IL-22, induction of IL-10R, strengthening of tight junctions and effects on colonic neurons. Several cell types depend on AHR signalling either for their survival (intraepithelial lymphocytes (IELs) and group 3 innate lymphoid cells (ILC3s)) or for their functional activity (T helper 17 (T_H17) cells, regulatory T (T_reg) cells and ILC2s). IL-22 is produced mainly by ILC3s under steady-state conditions and induces secretion of antimicrobial peptides by intestinal epithelial cells (IECs) for barrier protection. Following infection with pathogens such as Citrobacter rodentium, T_H17 cells take over from ILC3s as major producers of IL-22. T_reg cells will balance the inflammatory response via secretion of IL-10. Expression of AHR in colonic neurons supports motility, which increases gut microbiota density. b | AHR deficiency leads to perturbation of ILC balance, an increase in the numbers of eosinophils and neutrophils and a decrease in the numbers of ILC3s and IELs. This leads to a lack of IL-22, increased levels of proinflammatory cytokines (tumour necrosis factor (TNF), IL-6, IL-17 and interferon-γ (IFNγ)), vascular leakage, reduced mucus layer and disruption of the barrier (impairment of tight junctions). Lack of AHR in colonic neurons negatively affects gut motility (peristalsis) and leads to overgrowth of intestinal bacteria. EC, endothelial cell; ENS, enteric nervous system; ex-T_H17 cell, T_H17 cell secreting IFNγ due to plasticity; LTi, lymphoid tissue inducer.

Fig. 3. AHR function in intestinal epithelial cells.

In the absence of ligands (yellow), epithelial aryl hydrocarbon receptor (AHR) is inactive and sequestered in an actin-bound complex containing AHR-interacting protein (AIP), p23, SRC and heat shock protein 90 (HSP90), which maintains AHR in a configuration conducive to ligand binding while preventing proteasomal degradation. Upon ligand binding the complex translocates into the nucleus and AHR dimerizes with its nuclear-localized cofactor AHR nuclear translocator (ARNT) to drive transcription of AHR target genes. AHR signalling restrains stemness programmes through transcriptional regulation of factors such as RNF43, an E3 ubiquitin ligase, which counteracts WNT-β-catenin by degrading WNT receptors (for example, Frizzled (FZ)). It might also act post-transcriptionally as part of an E3 ubiquitin ligase complex containing cullin 4B ubiquitin ligase (CUL4B), which causes the proteasomal degradation of β-catenin in the cytosol. Furthermore, ligand-bound AHR also functions to promote barrier integrity by upregulation of tight junction proteins in intestinal epithelial cells. RSPO, R-spondin; Ub, ubiquitin.

Fig. 4. From the gut and beyond: systemic implications of AHR signalling in the intestine.

Aryl hydrocarbon receptor (AHR) signalling in the gut can protect against the development of diseases in distal sites. AHR ligands from microbial metabolism of dietary tryptophan activate astrocytes to limit experimental autoimmune encephalomyelitis (EAE)-driven central nervous system (CNS) inflammation by facilitating type I interferon signalling. Phagocytosis of apoptotic cell debris triggers AHR activation in a ToLL-Like receptor 9 (TLR9)-dependent manner and is required for acquisition of a tolerant phenotype in myeloid cells to prevent systemic lupus erythematous (SLE)-like autoimmunity. IL-22 release by group 3 innate lymphoid cells and T helper 17 cells in the intestine can limit atherosclerosis development through upholding barrier integrity and limiting the growth of proatherogenic microbiota. The gut microbiota-derived short-chain fatty acid butyrate enhances production of the serotonin-derived metabolite 5-hydroxyindoleacetic acid (5-HIAA), selecting for growth of microbiota capable of tryptophan metabolism. 5-HIAA drives AHR activity in B cells, which promotes regulatory B (B_reg) cell differentiation and suppression of inflammation in arthritis. AHR signalling in intestinal epithelial cells stimulates production of intestinal-derived incretins (for example, glucagon-like peptide 1 (GLP1)), leading to improved glucose metabolism and protection from liver steatosis in mice receiving a high-fat diet. Black lines indicate studies with a direct AHR link, dotted lines refer to hypothesized links based on AHR function.