The Environmental Sensor AHR Protects from Inflammatory Damage by Maintaining Intestinal Stem Cell Homeostasis and Barrier Integrity

摘要

class="head no_bottom_margin" id="sec1title">IntroductionThe intestinal epithelium constitutes a single-layer barrier that separates the mucosal immune system from trillions of commensal bacteria. Interactions between intestinal epithelial cells (IECs), immune cells, and the microbiota underlie the maintenance of intestinal homeostasis in steady state as well as upon perturbation by infection. The integrity of the intestinal barrier has substantial implications for health even beyond the intestine. Numerous genetic loci are known to contribute to the development of inflammatory bowel diseases such as Crohn’s disease or ulcerative colitis and the genetic susceptibility for disease is well documented (). However, environmental factors including smoking, diet, and use of antibiotics play a significant role in the etiology of intestinal disorders, and the molecular mechanisms underlying their impact remain poorly defined.The environmental sensor AHR is highly expressed at barrier sites such as the skin, lung, and gut. Although the AHR was originally described as a receptor for dioxin and other xenobiotics, it is now clear that physiological AHR ligands such as dietary components and tryptophan metabolites (, , , , , ) serve to drive beneficial functions of AHR in the immune system as well as in non-hematopoietic cells. In the context of intestinal homeostasis, Ahr deficiency has detrimental consequences associated with loss of intraepithelial lymphocytes and ILC3 and absence of IL-22 production (, , , ). An important aspect of AHR activation is the necessity for negative feedback regulation as prolonged stimulation has detrimental effects (, ). AHR activation induces expression of a family of cytochrome P450 enzymes (CYP1 family), which metabolize AHR ligands, thereby terminating the stimulus (). In support of this, we recently showed that selective overexpression of CYP1A1 in IECs (Villin^CreR26^LSL-Cyp1a1 mice) acts as a metabolic roadblock leading to insufficient AHR ligand supply to mucosal immune cells, thereby compromising ILC3- and Th17 cell-mediated immunity to enteric infection (). However, the expression of CYP1A1 along the crypt-villus axis in response to dietary AHR ligand exposure strongly suggests a role for AHR in IEC function beyond regulation of ligand supply to the host.The rapid regeneration of the intestinal epithelium is a highly coordinated process that is fueled by the proliferation of LGR5-expressing intestinal stem cells (ISCs) located at the bottom of each crypt (href="#bib2" rid="bib2" class=" bibr popnode">Barker et al., 2007). The Wnt-β-catenin pathway is crucial for the proliferation and maintenance of ISCs and is tightly regulated by E3 ubiquitin ligases RNF43 and ZNRF3, which target WNT receptors for degradation (href="#bib16" rid="bib16" class=" bibr popnode">Koo et al., 2012). Aberrant Wnt-β-catenin activation is a hallmark of colorectal cancers, highlighting the importance of this pathway in intestinal homeostasis (href="#bib28" rid="bib28" class=" bibr popnode">Novellasdemunt et al., 2015).Utilizing mouse models as well as intestinal organoid cultures, we found that AHR acts directly on IECs to restrict excessive proliferation of ISCs through regulation of Rnf43 and Znrf3 expression. As a consequence, Ahr deficiency in IECs compromised the ability of intestinal stem cells to repair and differentiate in response to tissue damage, leading to profound effects on resistance to infection and formation of colorectal cancer. These defects could be repaired by exposure to dietary AHR ligands in Villin^CreR26^LSL-Cyp1a1 mice, which have an intact Ahr, whereas Villin^CreAhr^fl/fl mice lacking Ahr in IECs could not be rescued.Thus, AHR fulfils a critical role in intestinal stem cells by calibrating their response to Wnt-β-catenin signals, thereby allowing coordinated stem cell renewal and differentiation.