Abstract
Airborne ozone exposure causes severe lung injury and inflammation. The aryl hydrocarbon Receptor (AhR) (1), activated in pollutant-induced inflammation, is critical for cytokine production, especially IL-22 and IL-17A. The role of AhR in ozone-induced lung inflammation is unknown. We report here that chronic ozone exposure activates AhR with increased tryptophan and lipoxin A4 production in mice. AhR−/− mice show increased lung inflammation, airway hyperresponsiveness, and tissue remodeling with an increased recruitment of IL-17A and IL-22-expressing cells in comparison to control mice. IL-17A- and IL-22-neutralizing antibodies attenuate lung inflammation in AhR−/− and control mice. Enhanced lung inflammation and recruitment of ILC3, ILC2, and T cells were observed after T cell-specific AhR depletion using the AhRCD4cre-deficient mice. Together, the data demonstrate that ozone exposure activates AhR, which controls lung inflammation, airway hyperresponsiveness, and tissue remodeling via the reduction of IL-22 expression.
Highlights
Ozone is an abundant air pollutant that causes respiratory inflammation
Using T cell-specific aryl hydrocarbon Receptor (AhR)-deficient mice (CD4cre AhRf/f), we showed that AhR present in T cells induces the indirect repression of IL-22 and IL-17A by mediation of the recruitment of T cells of IL-22+ or IL-17+ and ILC3 of IL-22+ or IL-17+
We report that tryptophan produced upon ozone exposure leads to AhR activation and IL-22 and IL-17A production in the lung, probably through the production of tryptophan metabolites
Summary
Ozone is an abundant air pollutant that causes respiratory inflammation. Peaks of ozone correlate with severe respiratory disease, morbidity, mortality [2, 3], and hospital admissions [4,5,6]. An increase of 10 μg/m3 of ozone exposure for 1 h daily induces an increase of 0.26% in mortality rate [7]. Ozone causes severe lung tissue damage, with inflammation and emphysema, loss of lung function, and airway hyperresponsiveness in human and mice [12,13,14]. In the absence of ligands, AhR resides in the cytoplasm under the control of a chaperone protein complex. The AhR complex translocates into the nucleus, the chaperones are
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