Tryptophan metabolite activation of the aryl hydrocarbon receptor regulates IL-10 receptor expression on intestinal epithelia

Abstract

IL10 is a potent anti-inflammatory cytokine that inhibits the production of pro-inflammatory mediators. Signaling by IL10 occurs through the IL10 receptor (IL10R), which is expressed in numerous cell types, including intestinal epithelial cells (IEC), where it is associated with development and maintenance of barrier function. Guided by an unbiased metabolomics screen, we identified tryptophan (Trp) metabolism as a major modifying pathway in IFN-γ-dominant murine colitis. In parallel, we demonstrated that IFN-γ induction of IDO1, an enzyme that catalyzes the conversion of Trp to kynurenine (Kyn), induces IL10R1 expression. Based on these findings, we hypothesized that IL10R1 expression on IEC is regulated by Trp metabolites. Analysis of the promoter region of IL10R1 revealed a functional aryl hydrocarbon response element (AHRE), which is induced by Kyn in luciferase-based IL10R1 promoter assays. Additionally, this analysis confirmed that IL10R1 protein levels were increased in response to Kyn in IEC in vitro. Studies utilizing in vitro wounding assays revealed that Kyn accelerates IL10-dependent wound closure. Finally, reduction of murine DSS colitis through Kyn administration correlates with colonic IL10R1 expression. Together, these results provide evidence on the importance of IL10 signaling in intestinal epithelia and implicate AHR in the regulation of IL10R1 expression in the colon.

Efficacy of Indigo Naturalis in a Multicenter Randomized Controlled Trial of Patients With Ulcerative Colitis

“…[24][25][26][27] More recently, IN has been shown to improve dextran sulfate sodium-induced colitis in a mouse model via an AhR/IL-22-mediated pathway. 28 However, recent studies have also shown other mechanisms of AhR signaling in terms of the induction of IL-10 receptor expression on intestinal epithelia, 29 IL-10 production in macrophages, 30 the induction of regulatory T cells, 31 and the negative regulation of the NLRP3 inflammasome. 32 Regardless, IN with different mechanisms from the current standard treatments may be beneficial for cases in which the efficacy of immunosuppressant or biologics is inadequate.…”

Biology and therapeutic potential of interleukin-10

“…Macrophage-derived IL-10 was shown to activate CREB signaling in intestinal epithelial cells, leading to the secretion of the WNT1-inducible signaling protein 1, which in turn induced epithelial cell proliferation and wound closure (Quiros et al, 2017). Furthermore, up-regulation of the IL-10R in intestinal epithelial cells has been described (Kominsky et al, 2014), and recent studies not only confirm the importance of the IL-10R in wound healing but also implicate tryptophan metabolites and AhR in its up-regulation (Lanis et al, 2017).…”

Tissue metabolism and the inflammatory bowel diseases

“…In colitis, these lymphocytes can then be transdifferentiated back toward Th1 cell types by Kyn signaling through AHR and contribute to the resolution of inflammation [75, 76]. Further contributing to resolution is the AHR induced expression of the IL-10 receptor (IL-10R1) on colonic epithelial cells [77]. IL-10 signaling is critical for colonic homeostasis and IL-10R1 expression on colonic epithelial cells helps regulate barrier formation [78].…”

“…IL-10 signaling is critical for colonic homeostasis and IL-10R1 expression on colonic epithelial cells helps regulate barrier formation [78]. Recent evidence demonstrates that exogenous Kyn enhances wound healing in an IL-10 dependent manner in vitro and alleviates DSS colitis in vivo [77]. …”