Regulation of the Immune Response by the Aryl Hydrocarbon Receptor

Abstract

The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that is activated by small molecules provided by the diet, microorganisms, metabolism, and pollutants. AhR is expressed by a number of immune cells, and thus AhR signaling provides a molecular pathway that integrates the effects of the environment and metabolism on the immune response. Studies have shown that AhR signaling plays important roles in the immune system in health and disease. As its activity is regulated by small molecules, AhR also constitutes a potential target for therapeutic immunomodulation. In this review we discuss the role of AhR in the regulation of the immune response in the context of autoimmunity, infection, and cancer, as well as the potential opportunities and challenges of developing AhR-targeted therapeutics.

Indoxyl sulfate–induced TNF‐α is regulated by crosstalk between the aryl hydrocarbon receptor, NF‐κB, and SOCS2 in human macrophages

“…S1A) and did not recover until later time points in both types of macrophages. It has been suggested that ligandbound AhR immediately translocates into the nucleus, where it forms a complex with ARNT (21,22,32). An immunoblot assay of nuclear and cytosolic fractions clearly shows that IS stimulation led to rapid translocation of AhR into the nucleus within 5 min (Supplemental Fig.…”

“…This complex binds an AhR-specific binding sequence [xenobiotic-responsive element (XRE) or dioxin-responsive element] present in the promoters of a wide variety of target genes. It has been demonstrated that AhR activation also initiates negative feedback loops that restrict AhR signaling via its time-dependent degradation by the 26S proteasome (21,22). In addition, AhR functions as a component of many signaling pathways through its interaction with other proteins independent of its ability to bind to DNA (18,23).…”

“…AhR is expressed by a variety of immune cells, and its signaling has integrative effects on the environment and metabolism of the immune response (21,22). In this context, a growing number of studies have investigated the immunologic role for AhR in the pathogenesis of many diseases (18,22,23).…”

“…AhR is expressed by a variety of immune cells, and its signaling has integrative effects on the environment and metabolism of the immune response (21,22). In this context, a growing number of studies have investigated the immunologic role for AhR in the pathogenesis of many diseases (18,22,23). Ligand-, tissue-, and cellspecific effects of AhR signaling control pathogenic activities by exerting both deleterious and protective immunologic effects (24)(25)(26)(27).…”

Tryptophan and arginine catabolic enzymes and regulatory cytokines in clinically isolated syndrome and multiple sclerosis

“…Increased IDO expression associates with tolerogenic pathways because of Trp depletion and has been associated with the formation of tolerogenic dendritic cells and induction of T regulatory (T reg ) cells 6, 7. Kynurenines are Trp metabolites that stimulate aryl hydrocarbon receptors and associated downstream immunoregulatory pathways 8, 9…”