The aryl hydrocarbon receptor in immune regulation and autoimmune pathogenesis

The aryl hydrocarbon receptor (AhR) is a member of the periodic circadian protein (PER)-AhR nuclear translocator (ARNT)-single-minded protein (SIM) superfamily of transcription factors, in which the PER-ARNT-SIM (PAS) domain senses both endogenous factors (such as oxygen tension or redox potential) and exogenous factors (such as poly-aromatic hydrocarbons and environmental toxins) [1]. Early studies on AhR were conducted to understand the mechanistic basis for the toxicity mediated by the prototypic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) [2,3]. Since the last decade, growing attention has been paid to the role of environmental pollutants (e.g. TCDD) in the development of immunological diseases including autoimmune disorders [4]. With the stimulation of exogenous AhR ligand (TCDD) in immunocompetent cell populations, AhR was found to regulate various biological processes, including development and homeostasis. For example, AhR plays a role in differentiating Th17 cells and regulatory T cells (Tregs) [5,6], maintaining innate lymphoid cells (ILCs) [7], mobilizing myeloid-derived suppressor cells (MDSCs) [8,9], and B-cell maturation [10,11].

Although AhR was originally thought only to mediate the toxic effects of dioxins, a variety of physiological ligands such as those derived from diet, symbiotic flora, and host metabolism also interact with AhR [1]. Many studies have shown that AhR directly or indirectly regulates numerous genes for various biological functions, including cell differentiation, malignant transformation, immune response regulation, circadian rhythm control, cell metabolism, adaptive and innate immunity [12,13]. The identification of natural ligands and analysis of AhR-deficient mice have demonstrated the important physiological role of AhR [14]. Recent studies suggest that the AhR signaling pathway may be implicated with autoimmune diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), Sjögren's syndrome (SS), multiple sclerosis (MS), autoimmune hepatitis (AIH), and inflammatory bowel disease (IBD). The AhR agonists or antagonists has been applicated in various autoimmune disease models. For example, phagocytosis of apoptotic cell fragments by macrophages triggers AhR signaling, and AhR activation induces the immunomodulatory cytokine IL-10, which suppresses the downstream inflammatory response to regulate immune tolerance in SLE [15]. Different AhR agonists such as TCDD and 6-formylindolo [3,2-b] carbazole (FICZ) play contrasting roles in experimental autoimmune encephalomyelitis (EAE), with the former inducing differentiation of Treg cells and inhibiting EAE, while the latter interfering with differentiation of Treg cells and promoting differentiation of Th17 cells and exacerbating EAE [5]. Moreover, increased availability of AhR ligand 5-Hydroxyindole-3-acetic acid (5-HIAA) promotes the regulation of Breg suppressor function and inhibits the differentiation of germinal center (GC) B cells and plasma cells, thereby ameliorating arthritic symptoms [16]. In contrast, the dysfunction of AhR signaling may be associated with impaired immunosuppressive function in some autoimmune diseases, for example, the defective response of Th17 cells of Crohn's disease to AhR signaling is manifested by impaired upregulation of extracellular enzymes-CD39 [17], which plays an immunosuppressive role, and similarly in Th17 and Treg cells of autoimmune hepatitis patients [18]. On the other hand, a recent study has shown that the dietary supplementation with the natural AhR ligand indole-3-propionic acid (IPA) improves salivary gland pathology and restores polymorphonuclear MDSCs (PMN-MDSCs) immunosuppressive function in ESS mice [19]. Many questions arose regarding the cellular and molecular consequences of AhR activation, but despite many investigations for almost two decades, the molecular basis by which AhR participates in immunological processes remains largely unknown [2].

In this review, we discuss the roles of AhR in regulating multiple immune cells and immune responses within the context of autoimmunity. Further understanding AhR regulation of immune cell and the effect of AhR agonists and antagonists will facilitate the development of new targeted therapies for the treatment of human disease.

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