Non-specific staining was blocked by incubating cells with an anti-mouse CD16/32 mAb


Non-specific staining was blocked by incubating cells with an anti-mouse CD16/32 mAb. immune-mediated pathologies and maintaining sufficient host defenses against contamination. Introduction 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 AHRs remarkable capacity to modulate T cell responses has been exhibited in autoimmune diseases1C5, allergic inflammation6,7, and inflammatory bowel diseases8C10. Yet, these reports also suggest that different AHR ligands may bias adaptive Cenerimod immune responses in opposite directions, and that exposure to the same ligand can worsen or improve pathology in different disease models1,2,11. 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 diseases12,13. Yet, there is another aspect of AHR immunobiology that has direct bearing around the potential success of new strategies to use AHR ligands as treatment modalities: the impact on host responses to contamination. Several reports demonstrate the importance of AHR in sensing microbes, including pathogenic and commensal bacteria, mycobacteria, and fungi14C17. 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 infections18,19. These observations have been extended with animal studies, showing that AHR modulates cell-mediated and humoral immune responses to contamination, and subsequently disease outcome20. A limitation of current information about AHR effects on adaptive immune responses during contamination is that much of this evidence stems from studies conducted when AHR is usually activated using the Rabbit Polyclonal to MAP3K4 high affinity binding environmental contaminant 2,3,7,8-tetrachlorodibenzo-consequences of treatment with four different agonists around the adaptive immune response to contamination with influenza A virus (IAV). To represent AHR binding compounds from different sources, we used 2,3,7,8-tetrachlorodibenzo-and metabolism and elimination: FICZ is usually rapidly cleared, whereas PCB126 and TCDD are slowly to poorly eliminated, respectively11,22,26. The absorption, metabolism, distribution, and excretion rates of ITE are undetermined. Based on chemical structure, it is predicted to be more rapidly metabolized than TCDD or PCB12625,27; thus, dosing was daily. As a way of establishing activation of the AHR, we confirmed that administration of all 4 compounds significantly increased expression in the liver (Fig.?1b). The induction of in mice treated with FICZ was lower in magnitude relative to mice treated with ITE, PCB126, or TCDD (a 2.5-fold versus??25-fold increase over vehicle; Fig.?1b, inset). Previous reports showed that TCDD increases morbidity, Cenerimod and sometimes mortality, following IAV contamination36C39. Therefore, we used a strain and dose of virus that causes a moderate contamination, in order to compare adaptive immune responses across the groups. With the virus inoculation used, only mice treated with TCDD exhibited severe weight loss (Fig.?1c), and none of the mice in any group died (data not shown). Yet, mice in all groups had comparable lung viral burdens (Fig.?1d). Open in a separate window Physique 1 administration activates AHR. (a) Dosing strategy: arrows depict when female C57Bl/6 mice were treated with each compound. The indicated Cenerimod times are relative to intranasal (i.n.) contamination with IAV, which is usually denoted as day 0. TCDD (10?g/kg BW) and PCB126 (100?g/kg BW) were administered orally once, one day before infection. FICZ (100?g/kg BW daily) was also administered by gavage, whereas ITE (10?mg/kg BW daily) was given intraperitoneally (i.p.). Structures for each compound are shown to the left of the dosing strategy ( Control mice received the appropriate vehicle following the same treatment route and dosing schedule: VEHFICZ, VEHITE, VEHDLC. The response of all vehicle treatment groups to.