The aryl hydrocarbon receptor/microRNA-212/132 axis in T cells regulates IL-10 production to maintain intestinal homeostasis

Abstract

Aryl hydrocarbon receptor (Ahr), a transcription factor, plays a critical role in autoimmune inflammation of the intestine. In addition, microRNAs (miRNAs), small non-coding oligonucleotides, mediate pathogenesis of inflammatory bowel diseases (IBD). However, the precise mechanism and interactions of these molecules in IBD pathogenesis have not yet been investigated. We analyzed the role of Ahr and Ahr-regulated miRNAs in colonic inflammation. Our results show that deficiency of Ahr in intestinal epithelial cells in mice exacerbated inflammation in dextran sodium sulfate-induced colitis. Deletion of Ahr in T cells attenuated colitis, which was manifested by suppressed Th17 cell infiltration into the lamina propria. Candidate miRNA analysis showed that induction of colitis elevated expression of the miR-212/132 cluster in the colon of wild-type mice, whereas in Ahr (-/-) mice, expression was clearly lower. Furthermore, miR-212/132(-/-) mice were highly resistant to colitis and had reduced levels of Th17 cells and elevated levels of IL-10-producing CD4(+) cells. In vitro analyses revealed that induction of type 1 regulatory T (Tr1) cells was significantly elevated in miR-212/132(-/-) T cells with increased c-Maf expression. Our findings emphasize the vital role of Ahr in intestinal homeostasis and suggest that inhibition of miR-212/132 represents a viable therapeutic strategy for treating colitis.

AHR Activation Is Protective against Colitis Driven by T Cells in Humanized Mice

“…Many of these mutations are known to regulate immune responses with several being enriched in immune cells, in particular CD4 + T cells and dendritic cells (Jostins et al, 2012). Although polymorphisms in AHR have not yet been associated with IBD, AHR is known to play a central role in the regulation of intestinal inflammation and is upregulated in the inflamed gut (Arsenescu et al, 2011; Benson and Shepherd, 2011; Chinen et al, 2015; Fukumoto et al, 2014; Furumatsu et al, 2011; Huang et al, 2013; Ji et al, 2015; Mascanfroni et al, 2015; Monteleone et al, 2011; Qiu et al, 2013; Quintana et al, 2012; Singh et al, 2011; Takamura et al, 2011; Takamura et al, 2010; Yeste et al, 2014). We and others previously showed that in T cells, AHR controls the production of IL-10 (Apetoh et al, 2010; Gandhi et al, 2010; Mascanfroni et al, 2015; Wu et al, 2011) and IL22 (Quintana et al, 2008; Veldhoen et al, 2009; Veldhoen et al, 2008; Yeste et al, 2014) to modulate and promote immunological tolerance in the intestine.…”

“…Previous work from our group and others demonstrates a role for AHR in the differentiation and function of Tregs and effector T cells by controlling the production of IL-10 and IL-22 (Apetoh et al, 2010; Gandhi et al, 2010; Quintana et al, 2008; Yeste et al, 2014) (Mascanfroni et al, 2015). In mice, activation of AHR suppresses experimental colitis and, although there are no current therapies that target AHR in humans, the expression of AHR is increased in IBD lesions (Arsenescu et al, 2011; Benson and Shepherd, 2011; Chinen et al, 2015; Fukumoto et al, 2014; Furumatsu et al, 2011; Monteleone et al, 2011). Given the importance of Tregs in intestinal homeostasis, coupled with the immunomodulatory effects of IL-10 and IL-22 downstream of AHR activation (Mayne and Williams, 2013; Sonnenberg et al, 2011), AHR is an attractive therapeutic target.…”

Transcription factor c‐Maf is essential for IL‐10 gene expression in B cells

“…Although c‐Maf can transactivate IL‐10 by itself to some extent, robust IL‐10 expression requires interaction with additional transcriptional regulators. In the case of Tr1 cells generated in the presence of IL‐27 or IL‐27/TGF‐ β , c‐Maf cooperates with AhR in the regulation of IL‐10 production in mice as well as humans . In the presence of LPS, the expression of c‐Maf improved markedly in B cells and was followed by increased production of IL‐10.…”

Novel Aryl Hydrocarbon Receptor Agonist Suppresses Migration and Invasion of Breast Cancer Cells

“…In this study, we show consistent results using Flavipin as a novel Ahr agonist. The miRNAs are small non-coding RNAs that are emerging as a new avenue to provide mechanistic explanations for different modulatory effects of Ahr [9, 46, 47]. In this regard, our previous report provided a miR-based mechanistic explanation for the inhibitory role of natural and synthetic Ahr agonists on invasion of MDA-MB-231 and T47D cells [16].…”