Activation of Aryl Hydrocarbon Receptor by Tcdd Prevents Diabetes in Nod Mice and Increases Foxp3 ⁺ T Cells in Pancreatic Lymph Nodes

Abstract

The ligand-activated transcription factor, aryl hydrocarbon receptor (AHR), is a novel inducer of adaptive Tregs. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), the most potent AHR ligand, induces adaptive CD4+CD25+ Tregs during an acute graft-versus-host (GvH) response and prevents the generation of allospecific cytotoxic T lymphocytes. TCDD also suppresses the induction of experimental autoimmune encephalitis in association with an expanded population of Foxp3+ Tregs. In this study, we show that chronic treatment of NOD mice with TCDD potently suppresses the development of autoimmune Type 1 diabetes in parallel with greatly reduced pancreatic islet insulitis and an expanded population of CD4+CD25+Foxp3+ cells in the pancreatic lymph nodes. When treatment with TCDD was terminated after 15 weeks (23 weeks of age), mice developed diabetes over the next 8 weeks in association with lower numbers of Tregs and decreased activation of AHR. Analysis of the expression levels of several genes associated with inflammation, T-cell activation and/or Treg function in pancreatic lymph node cells failed to reveal any differences associated with TCDD treatment. Taken together, the data suggest that AHR activation by TCDD-like ligands may represent a novel avenue for treatment of immune-mediated diseases.

Nanovesicles From Lactobacillus johnsonii N6.2 Reduce Apoptosis in Human Beta Cells by Promoting AHR Translocation and IL10 Secretion

“…As such, AHR signaling has been recognized as a key regulator of several immune diseases, however, current literature regarding the impact of AHR activation on the pathogenesis of type 1 diabetes suggests that its effect is indirect through immune modulation and not directly on beta cells. As an example, administration of the AHR agonist TCDD prevented diabetes onset in NOD mice by increasing the frequency of Foxp3+T cells in pancreatic lymph nodes ( 39 ). In agreement with this finding, in other models of autoimmunity, AHR activation with 6-formylindolo[3,2-b] carbazole (FICZ) and 2,(1’H’indole, 3’ carbonyl) thiazole-4-carboxylic acid methyl ester (ITE) was correlated with reduced dendritic cell antigen presentation, as well as T H 1 and T H 17 cell activation ( 40 ).…”

Aryl hydrocarbon receptor (AhR) activation contributes to high‐fat diet‐induced vascular dysfunction

“…AhR signalling regulates many physiological and pathological processes, including innate and adaptive immune responses (Kerkvliet et al, 2009; Lawrence et al, 2008; Rothhammer & Quintana, 2019), maintenance of intestinal epithelial cells integrity (Metidji et al, 2018) and homeostasis of the cardiovascular system (Zhang, 2011). AhR is an environment sensor that integrates environmental, dietary, microbial and metabolic signals to control a complex transcriptional cellular response (Kerkvliet et al, 2009; Rothhammer & Quintana, 2019; Zhang, 2011). AhR activation by agonists in cigarette smoke, for example, exacerbates experimental autoimmunity by enhancing pathogenic TH17 cell generation (Talbot et al, 2018).…”

TCDD Inhibition of IgG1 Production in Experimental Autoimmune Encephalomyelitis (EAE) and In Vitro

“…Part of the pathophysiology of EAE involves production of pathogenic antibodies that can recruit cytolytic cells to destroy MOG-expressing cells that comprise myelin, so inhibition of IgG1 likely contributes to TCDD’s disease attenuation. Moreover, these data suggest that suppression of IgG1 might also account for TCDD’s ability to suppress other autoimmune disease models such as autoimmune type 1 diabetes [ 37 ], autoimmune uveoretinitis [ 38 ], and murine systemic lupus erythematosus [ 39 ]. These studies further suggest that less toxic AhR ligands that attenuate autoimmune disease could possess efficacy as immunosuppressants through suppression of IgG1.…”