Aryl hydrocarbon receptor signaling modulates antiviral immune responses: ligand metabolism rather than chemical source is the stronger predictor of outcome

Abstract

The aryl hydrocarbon receptor (AHR) offers a compelling target to modulate the immune system. AHR agonists alter adaptive immune responses, but the consequences differ across studies. We report here the comparison of four agents representing different sources of AHR ligands in mice infected with influenza A virus (IAV): TCDD, prototype exogenous AHR agonist; PCB126, pollutant with documented human exposure; ITE, novel pharmaceutical; and FICZ, degradation product of tryptophan. All four compounds diminished virus-specific IgM levels and increased the proportion of regulatory T cells. TCDD, PCB126 and ITE, but not FICZ, reduced virus-specific IgG levels and CD8 + T cell responses. Similarly, ITE, PCB126, and TCDD reduced Th1 and Tfh cells, whereas FICZ increased their frequency. In Cyp1a1-deficient mice, all compounds, including FICZ, reduced the response to IAV. Conditional Ahr knockout mice revealed that all four compounds require AHR within hematopoietic cells. Thus, differences in the immune response to IAV likely reflect variances in quality, magnitude, and duration of AHR signaling. This indicates that binding affinity and metabolism may be stronger predictors of immune effects than a compound's source of origin, and that harnessing AHR will require finding a balance between dampening immune-mediated pathologies and maintaining sufficient host defenses against infection.There is considerable evidence that signaling through the aryl hydrocarbon receptor (AHR) alters the course of adaptive immune responses in a manner that can be protective or detrimental. Adaptive immune responses underlie host protection from pathogens, but when improperly controlled they contribute to numerous diseases. The AHR's remarkable capacity to modulate T cell responses has been demonstrated in autoimmune diseases 1-5 , allergic inflammation 6,7 , and inflammatory bowel diseases [8][9][10] . Yet, these reports also suggest that different AHR ligands may bias adaptive immune responses in opposite directions, and that exposure to the same ligand can worsen or improve pathology in different disease models 1,2,11 . While these issues remain to be resolved, the ability of the AHR to modulate T cell differentiation and T cell-dependent immune responses has generated enthusiasm about targeting therapeutic agents at the AHR in order to modulate the progression of a large spectrum of immune-mediated diseases 12,13 .Yet, there is another aspect of AHR immunobiology that has direct bearing on the potential success of new strategies to use AHR ligands as treatment modalities: the impact on host responses to infection. Several reports demonstrate the importance of AHR in sensing microbes, including pathogenic and commensal bacteria, mycobacteria, and fungi [14][15][16][17] . Epidemiological studies show strong correlations between exposure to anthropogenically-derived AHR ligands from the environment and increased incidence and severity of respiratory infections, most notably viral infections 18,19 . These observations have been extended with a...

Melatonin: Roles in influenza, Covid‐19, and other viral infections

“…This study also showed that the AhR modulates macrophage and dendritic cell responses, including the levels of interleukin (IL)-1β, IL-10, and tumor necrosis factor (TNF)α 23. Other data show the different AhR ligands differentially modulate immunoglobulin (Ig)G and CD8+ T-cell responses to the influenza virus, with the loss of CYP1 attenuating AhR-driven effects on virusdriven immune responses 20. Whether such AhR-driven effects are regulated by variations in the mitochondrial melatonergic pathway and NAS/melatonin ratio requires investigation, including as to the relevance of these AhR-associated pathways in covid-19 infection.…”

“…tetrachlorodibenzo-p-dioxin (TCDD), commonly found in cigarette smoke; polychlorinated biphenyl congener 126 (PCB126), a common pollutant; the novel pharmaceutical, 2-(1 0 H-indole-3 0 -carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE); and the endogenous AhR ligand, 6-formylindolo[3,2-b]carbazole (FICZ), which is a tryptophan degradation product. All of these ligands can modulate immune responses to viral infection 20,21. However, it is the activation of the AhR by kynurenine and kynurenic acid that more readily links the AhR to immune inflammatory activity, as shown inFigure 1.…”

Genome-Wide Transcriptional Analysis Reveals Novel AhR Targets That Regulate Dendritic Cell Function during Influenza A Virus Infection

“…Consistent with this idea, in the context of IAV infection AhR activation significantly impairs the ability of DCs to activate virus-specific CD8 + T cells via a mechanism that is in part because of to AhR-mediated events in DCs (25). This is likely not an effect that is unique to the prototype AhR agonist TCDD, as other AhR ligands cause similar changes in T cell responses to IAV infection (37). Also, soybean tar extract, which contains AhR agonists, dampened CCL17 production by mouse bone marrow-derived DCs, although it is not certain that this occurred in an AhR-dependent mechanism (86).…”

“…Dr. C. Bradfield (University of Wisconsin, Madison, WI) provided breeding stock of Ahr dbd , Ahr KO , and Ahr fx/fx mice, and colonies are continually maintained at the University of Rochester Medical Center. Vav1 cre Ahr fx/fx (Ahr DVav1 ) were created by crossing female Ahr fx/fx mice with male Vav1 cre transgenic mice (37). All mice are housed in microisolator cages in a specified pathogen?-free facility at the University of Rochester Medical Center and are provided food and water ad libitum.…”

The tryptophan derivative 6-formylindolo[3,2-b]carbazole, FICZ, a dynamic mediator of endogenous aryl hydrocarbon receptor signaling, balances cell growth and differentiation

“…In other mice infected with the influenza A virus, ten daily i.p. administrations of 100 lg FICZ kg À1 attenuated virus-specific immunoglobulin M (IgM) levels and elevated the proportion of Treg cells, without reducing CD8 þ T cell responses (Boule et al 2018). In other studies, treatment of mice with 2 mg FICZ (about 100 mg kg À1 ) suppressed immune responses to the influenza A, vesicular stomatitis, and Sendai viruses (Yamada et al 2016), whereas treatment of mice infected with ocular herpes simplex virus intraperitoneally with 1 mg FICZ each (about 50 mg kg À1 ) once every day for eleven consecutive days had no effect on the occurrence of ocular lesions (Veiga-Parga et al 2011).…”