Dietary Indoles Suppress Delayed-Type Hypersensitivity by Inducing a Switch from Proinflammatory Th17 Cells to Anti-Inflammatory Regulatory T Cells through Regulation of MicroRNA

Abstract

Aryl hydrocarbon receptor (AhR) has been shown to have profound influence on T cell differentiation and use of distinct AhR ligands has shown that while some ligands induce Tregs, others induce Th17 cells. In the current study, we tested the ability of dietary AhR ligands (indole-3-carbinol; I3C and 3,3'-diindolylmethane; DIM), and an endogenous AhR ligand, 6-Formylindolo(3,2-b)carbazole (FICZ), on the differentiation and functions of Tregs and Th17 cells. Treatment of C57BL/6 mice with indoles (I3C or DIM), attenuated DTH response to mBSA and generation of Th17 cells while promoting Tregs. In contrast, FICZ exacerbated the DTH response and promoted Th17 cells. Indoles decreased the induction of IL-17 while promoted IL-10 and FoxP3 expression. Also, indoles caused reciprocal induction of Tregs and Th17 cells only in wild-type (AhR+/+) but not in AhR knockout (AhR−/−) mice. Upon analysis of microRNA (miR) profile in draining lymph nodes of mice with DTH, treatment with I3C and DIM decreased the expression of several miRs (miR-31, miR-219, and miR-490) that targeted FoxP3, while increasing the expression of miR-495 and miR-1192 that were specific to IL-17. Interestingly, treatment with FICZ had precisely the opposite effects on these miRs. Transfection studies using mature miR mimics of miR-490 and miR-1192 that target FoxP3 and IL-17 respectively or scrambled miR (mock) or inhibitors confirmed that these miRs specifically targeted FoxP3 and IL-17 genes. Our studies demonstrate for the first time that the ability of AhR ligands to regulate the differentiation of Tregs versus Th17 cells may depend on miR signature profile.

Immune regulation by microbiome metabolites

“…AhR activation promotes monocyte differentiation into DCs over macrophages . In vivo , dietary indoles suppress Th17 but increase Treg responses . Thus, the effects of AhR ligands on T‐cell responses are complex, mediated by many factors and cell types.…”

The role of gut microbiome and associated metabolome in the regulation of neuroinflammation in multiple sclerosis and its implications in attenuating chronic inflammation in other inflammatory and autoimmune disorders

“…Some of the known side‐chain functional groups include, but are not limited to, acetate, aldehyde and propionate . These indole‐based by‐products have the capability to bind as well as activate the aryl hydrocarbon receptor (AHR) present in host lymphocytes, similar to plant‐derived indoles . The AHR is a cytosolic receptor that upon activation undergoes conformational changes, binds a carrier protein to import it into the nucleus, and carries out an effector function within the nucleus as a transcription factor .…”

“…Modulation of AHR activity through ligand binding by environmental pollutants such as 2,3,7,8‐tetrachlorodibenzodioxin to dietary indoles has been shown primarily to lead to induction of Treg cells . However, some endogenous ligands such as 6‐formylindolo[3,2‐b]carbazole have also been shown to induce Th17 cells . The ability of AHR ligands to induce Treg cells versus Th17 cells may depend on their capacity to cause epigenetic changes including microRNA, and clearly more research is needed to understand the complexity of the receptor.…”

Comprehensive analysis of differential circular RNA expression in a mouse model of colitis‐induced colon carcinoma

“…For example, mmu_circRNA_001226 is predicted to be able to bind to 55 mmu-miRNA, including mmu-miR-1192, mmu-miR-1224-5p, mmu-miR-25-3p, mmu-miR-23a-3p, and mmu-miR-192-3p. Regulation of miR-1192 is related to proinflammatory Th17 cell differentiation 29 while Th17 cells are involved in inflammation associated colon carcinogenesis. 30 miR-1224-5p expression was associated with a specific predictor of the response to chemoradiotherapy in rectal cancer patients, 31 and fecal miR-1224-5p expression could be a potential, noninvasive marker of microbial fluctuations alone with gut pathology in the intestine.…”