Abstract
The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the metabolism of xenobiotics. There is growing evidence that the AhR is implicated in physiological processes such proliferation, differentiation, and immune responses. Recently, a role of the AhR in regulating allergic asthma has been suggested, but whether the AhR also regulates other type of asthma, particularly occupational/irritant-induced asthma, remains unknown. Using AhR-deficient (Ahr−/−) mice, we compared the function of the AhR in the response to ovalbumin (OVA; allergic asthma) vs. chlorine (Cl2; irritant-induced asthma) exposure. Lung inflammation and airway hyperresponsiveness were assessed 24h after exposure to Cl2 or OVA challenge in Ahr−/− and heterozygous (Ahr+/−) mice. After OVA challenge, absence of AhR was associated with significantly enhanced eosinophilia and lymphocyte influx into the airways of Ahr−/− mice. There were also increased levels of interleukin-4 (IL-4) and IL-5 in the airways. However, OVA-induced airway hyperresponsiveness was not affected. In the irritant-induced asthma model caused by exposure to Cl2, the AhR did not regulate the inflammatory response. However, absence of AhR reduced Cl2-induced airway hyperresponsiveness. Collectively, these results support a differential role for the AhR in regulating asthma outcomes in response to diverse etiological agents.
Highlights
Exposure of the lungs to environmental toxicants such as pesticides, solvents, and air pollutants may lead to acute and chronic pulmonary inflammation that is associated with the development of asthma (Wong et al, 2016)
The aryl hydrocarbon receptor (AhR) has been largely associated with xenobiotic metabolism leading to toxicity, we have shown that the AhR suppresses the development of chronic obstructive pulmonary disease (COPD; Guerrina et al, 2021), an obstructive lung disease caused predominantly by cigarette smoke
While there was no difference in macrophage numbers (Figure 1C), there were significantly more eosinophils and lymphocytes in the airways of mice sensitized and challenged with OVA in both Ahr−/− and Ahr+/− mice compared with PBS control mice (Figures 1D,E)
Summary
Exposure of the lungs to environmental toxicants such as pesticides, solvents, and air pollutants may lead to acute and chronic pulmonary inflammation that is associated with the development of asthma (Wong et al, 2016). Neutrophilic-asthma (non-eosinophilic) is triggered by Th1 and Th17 lymphocytes with the release of cytokines (e.g., IFN-γ and IL-17) which favor the development of a cellular immune response, activation of macrophages, and release of neutrophil chemokines (Papi et al, 2018). Environmental stimuli such as chlorine (Cl2) can trigger Th1 and Th17-mediated airway inflammation that is implicated in the development of severe neutrophilic asthma (Fisk et al, 2010; Pelaia et al, 2015). Exposure to environmental toxicants contributes to the increasing prevalence of asthma, but these exposures can affect disease outcomes
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