Editorial: Role of the Aryl Hydrocarbon Receptor in Immune Modulation

The aryl hydrocarbon receptor (AhR), originally discovered as a xenobiotic receptor involved in upregulating metabolic enzymes, has become increasingly linked to physiological processes (McMillan and Bradfield, 2007;Okey, 2007;Abel and Haarmann-Stemmann, 2010;Wang et al., 2017;Roman et al., 2018;Rothhammer and Quintana, 2019).The discovery of endogenous, dietary and bacterial-derived ligands for the AhR further supports its involvement in the homeostatic regulation of biological processes (Adachi et al., 2001;Denison et al., 2011;Bessede et al., 2014;Faber et al., 2018;Rannug and Rannug, 2018;Doan et al., 2020).Yet, dysregulation of many of these processes can lead to disease states involving the immune system.Indeed, a toxicological and/or physiological role for the AhR in almost every facet of the immune system has emerged over the past 2 decades.Now, in addition to the AhR being an environmental sensor and mediator of toxicity, this enigmatic protein has emerged as a potential therapeutic target (Murray et al., 2010;Merches et al., 2017;Marafini et al., 2019;Safe et al., 2020;Esser, 2021;Lebwohl et al., 2021).However, many questions remain regarding the interplay between the toxicological and physiological functions of the AhR as well as the molecular mechanisms by which the AhR mediates its pleiotropic effects on immunity.In this special issue, three original research papers explored the role of the AhR in celland organ-specific immune responses.Further, two review papers described the role of the AhR as an environmental sensor in the eye as well as the skin and gut.Over the past decade, the AhR has emerged as a physiological regulator of specific T-cell and innate lymphoid cell (ILC) subtypes (Kiss et al., 2011;Lee et al., 2011;Qiu et al., 2012;Gutiérrez-Vázquez and Quintana, 2018).Until recently, there was negligible information on the AhR in different human B-cell subpopulations.Blevins et al., using human peripheral blood B cells, examined the role of the AhR in a specific B cell subtype, called CD5 + "innate-like" B cells (ILB).Although human CD5 + B cells are still poorly understood and appear to differ markedly from mouse CD5 + B cells, the authors discovered a significant correlation between the percent of CD5 + B cells and inhibition of IgM secretion by the high affinity AhR ligand TCDD.Furthermore CD5 - conventional B cells were resistant to the inhibitory effect of TCDD.When considering that CD5 + B cells appear to play an important protective role against bacterial pathogens, especially in children and the elderly, these results support a potential impairment in this protection upon exposure to environmental AhR ligands.While the previous publication highlighted a novel role for the AhR in a B cell subtype that bridges adaptive and innate immunity, the publication by Ishihara et al. reinforces the importance of the AhR in innate immunity, and in particular macrophage production of IL-22.The function of IL-22 may be pro-or anti-inflammatory, the nature of which may be context, organ and/or disease-specific.

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