An endogenous aryl hydrocarbon receptor ligand, ITE, induces regulatory T cells and ameliorates experimental colitis

Abstract

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that affects millions of people with high morbidity and health care costs. The precise etiology of IBD is unknown, but clear evidence suggests that intestinal inflammation is caused by an excessive immune response to mucosal antigens. Recent studies have shown that activation of the aryl hydrocarbon receptor (AhR) induces regulatory T cells (Tregs) and suppresses autoimmune diseases. In the current study, we investigated if a nontoxic ligand of AhR, 2-(1' H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), can attenuate dextran sodium sulfate-induced colitis. Our studies demonstrated that in mice that received ITE treatment in vivo, colitis pathogenesis, including a decrease in body weight, was significantly reversed along with the systemic and intestinal inflammatory cytokines. ITE increased the expression of Tregs in spleen, mesenteric lymph nodes (MLNs), and colon lamina propria lymphocytes (cLPL) of mice with colitis when compared with controls. This induction of Tregs was reversed by AhR antagonist treatment in vitro. ITE treatment also increased dendritic cells (CD11c) and decreased macrophages (F4/80) from the spleen, MLNs, and cLPL in mice with colitis. ITE also reversed the systemic and intestinal frequency of CD4 T cells during colitis and suppressed inflammatory cytokines including IFN-γ, TNF-α, IL-17, IL-6, and IL-1 as well as induced IL-10 levels. These findings suggest that ITE attenuates colitis through induction of Tregs and reduction in inflammatory CD4 T cells and cytokines. Therefore, our work demonstrates that the nontoxic endogenous AhR ligand ITE may serve as a therapeutic modality to treat IBD. NEW & NOTEWORTHY We report the novel finding that activation of the aryl hydrocarbon receptor with the nontoxic ligand 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) induces regulatory T cells (Tregs) and suppresses inflammatory bowel disease (IBD). Our data suggest that ITE diminishes colitis pathology through induction of Tregs; reduces inflammatory cytokines, inflammation score, and macrophage frequency; and induces DCs resulting in amelioration of colitis. Therefore, nontoxic endogenous ITE promotes the induction of Tregs and may be useful for the treatment of IBD.

Targeted deletion of the aryl hydrocarbon receptor in dendritic cells prevents thymic atrophy in response to dioxin

“…The estimated half-life of TCDD is approximately 10 days in mice (Birn-baum 1986;Gasiewicz et al 1983), whereas the in vivo absorption, metabolism, distribution, and excretion rates of ITE and I3C in mice remain largely undetermined. There fore, the selected doses and routes of exposure for these AhR ligands were based upon previous reports, thus integrating our results with previous findings in other model systems (Abron et al 2018;Benson and Shepherd 2011a;Boule et al 2018b;Nugent et al 2013;Quintana et al 2010b;Singh et al 2016).…”

“…2). To test the hypothesis that ITE induces thymic atrophy in an AhRdependent manner, C57Bl/6 and low affinity AhR d mice were gavaged daily with a previously described immunosuppressive dose of ITE (Abron et al 2018;Henry et al 2006;Nugent et al 2013;Quintana et al 2010b) and thymi analyzed 7 days later. ITE exposure to naive C57Bl/6 mice resulted in thymic atrophy as evidenced by a significant decline in organ weight (49% decrease) and a reduction in thymic cellularity (73% decrease) relative to vehicle control.…”

“…Although the precise cellular and molecular mechanisms involved remain largely unknown, previous studies demonstrated that the target for TCDDinduced thymic atrophy resides within the hematopoietic compartment and implicated reduced proliferation of DN precursor thymocytes (Lai et al 1994), enhanced apoptosis via Fas:FasL interactions at the DP stage (Camacho et al 2005b), and enhanced emigration of thymocytes (Temchura et al 2005), or a combination of these possible mechanisms. Therefore, it was of great interest to evaluate whether an endogenous, non-toxic AhR ligand 2-(1H-indol-3-ylcarbonyl)-4-thiazolecarboxylic acid methyl ester (ITE) (Abron et al 2018;Benson and Shepherd 2011b;Song et al 2002) and a dietary AhR ligand, indole 3-carbinol (I3C) (Benson and Shepherd 2011b;Bjeldanes et al 1991;Connor and Finley 2003) exhibited thymotoxic effects similar to TCDD. Furthermore, we assessed naive wild-type mice (C57Bl/6), mice expressing the low affinity AhR (AhR d ), and AhR conditional knock out mice (LyzM Cre AhR fx , CD11c Cre AhR fx , RORc Cre AhR fx , and FoxN1 Cre AhR fx ) to identify the target(s) specifically responsible for mediating TCDD-induced thymic atrophy.…”

The role of interleukin 22 in multiple sclerosis and its association with c-Maf and AHR

“…AHR may not be necessary for the effect, but it was also noted that AHR antagonists cause significant decrease in the speed of the process. The use of ITE, another AHR agonist, also causes an increase in Treg percentage 71 . It appears that the exact effect of AHR agonist depends on the dose and time of the AHR activation.…”

Aryl Hydrocarbon Receptor Activation Ameliorates Experimental Colitis by Modulating the Tolerogenic Dendritic and Regulatory T Cell Formation

“…AhR ligands, such as FICZ and ITE, have been shown to attenuate experimental colitis and restore the Th17 /Treg cell balance by inhibiting Th17 cell differentiation and promoting Treg cell formation (13,14). A previous study demonstrated that ITE could inhibit T cell-mediated immunity by acting on the DCs (15). Another study found that FICZ could inhibit DC-primed Th17 polarization from naïve T cells (16).…”