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Tryptophan Metabolite Activation of the Aryl Hydrocarbon Receptor in Intestinal Epithelia Promotes Mucosal Healing
Author(s) -
Lanis Jordi M,
Alexeev Erica,
Colgan Sean
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.465.9
Subject(s) - aryl hydrocarbon receptor , inflammation , kynurenine , inflammatory bowel disease , colitis , kynurenine pathway , biology , immunology , signal transduction , intestinal mucosa , receptor , transcription factor , microbiology and biotechnology , medicine , biochemistry , tryptophan , disease , amino acid , gene
Inflammatory bowel disease (IBD) is a chronic inflammation of the intestine affecting more 1 million people in the United States. The pathogenesis of IBD is not completely understood, but complex risk factors such as genetics, environmental exposures, diet, and changes to the microbiota all play a role in the establishment of this disease. Regardless of the triggering factors, it is clear that the response of intestinal epithelia to the various inflammatory signals is crucial to restore homeostasis. Significant shifts in tissue metabolism are detected during inflammation and include a notable increase in tryptophan (Trp) metabolites. In vivo work has demonstrated that inflammation stimulates the induction of epithelial indoleamine 2,3‐dioxygenase (IDO1), the enzyme that catalyzes the conversion of Trp to kynurenine (Kyn). Consequently, elevated levels of intracellular kynurenine trigger activation of the Aryl Hydrocarbon Receptor (AHR). Numerous pathways are mediated by the transcription factor AHR, but preliminary data suggests that AHR activation during colonic inflammation is important for IL10 receptor (IL10R1) expression and wound healing. Based on these findings, we hypothesized that epithelial AHR signaling is protective in colitis. To that end, in vivo studies have revealed that Kyn mediates protective actions via the AHR to ameliorate colitis in an IL10R1 dependent manner. In contrast, colitis in intestinal epithelia conditional AHR knockout mice is not improved with exogenous Kyn, and the isolated colonic epithelial cells are deficient in IL10R1. Together, these results provide evidence on the importance of AHR signaling in intestinal epithelia and implicate AHR in the regulation of IL10R1 expression in the colon. Support or Funding Information This work was supported by NIH grants DK099452, DK50189, DK095491, VA Merit BX002182 and by the Crohn's and Colitis Foundation of America.