The Endogenous Th17 Response in NO2-Promoted Allergic Airway Disease Is Dispensable for Airway Hyperresponsiveness and Distinct from Th17 Adoptive Transfer

Abstract

Severe, glucocorticoid-resistant asthma comprises 5-7% of patients with asthma. IL-17 is a biomarker of severe asthma, and the adoptive transfer of Th17 cells in mice is sufficient to induce glucocorticoid-resistant allergic airway disease. Nitrogen dioxide (NO2) is an environmental toxin that correlates with asthma severity, exacerbation, and risk of adverse outcomes. Mice that are allergically sensitized to the antigen ovalbumin by exposure to NO2 exhibit a mixed Th2/Th17 adaptive immune response and eosinophil and neutrophil recruitment to the airway following antigen challenge, a phenotype reminiscent of severe clinical asthma. Because IL-1 receptor (IL-1R) signaling is critical in the generation of the Th17 response in vivo, we hypothesized that the IL-1R/Th17 axis contributes to pulmonary inflammation and airway hyperresponsiveness (AHR) in NO2-promoted allergic airway disease and manifests in glucocorticoid-resistant cytokine production. IL-17A neutralization at the time of antigen challenge or genetic deficiency in IL-1R resulted in decreased neutrophil recruitment to the airway following antigen challenge but did not protect against the development of AHR. Instead, IL-1R-/- mice developed exacerbated AHR compared to WT mice. Lung cells from NO2-allergically inflamed mice that were treated in vitro with dexamethasone (Dex) during antigen restimulation exhibited reduced Th17 cytokine production, whereas Th17 cytokine production by lung cells from recipient mice of in vitro Th17-polarized OTII T-cells was resistant to Dex. These results demonstrate that the IL-1R/Th17 axis does not contribute to AHR development in NO2-promoted allergic airway disease, that Th17 adoptive transfer does not necessarily reflect an endogenously-generated Th17 response, and that functions of Th17 responses are contingent on the experimental conditions in which they are generated.

BCL-2 protects human and mouse Th17 cells from glucocorticoid-induced apoptosis

“…These additional cell types are potential targets for glucocorticoid regulation. The reduced number of IL-17A-expressing cells in certain patients and reduced IL-17A levels in several animal models (35, 36) by glucocorticoids could also be due to glucocorticoid inhibition of trafficking and recruitment of inflammatory cells (37, 38). In contrast to suppression of the recruitment of most leukocytes, a recent report suggests that glucocorticoids actually promote Th17 attraction and retention via upregulation of the airway epithelial production of CCL20 (23), the ligand for CCR6 on Th17 cells.…”

Environmental Pollution and the Developing Lung

“…The mechanisms by which this effect takes place appears to differ from allergic asthma in that the typical endogenous response of T-helper (Th)2/Th17 is not required. 32 As NO 2 is likely acting as an oxidant, there may be several mechanisms that could contribute.…”

Acute nitrogen dioxide (NO2) exposure enhances airway inflammation via modulating Th1/Th2 differentiation and activating JAK-STAT pathway

“…Previous studies demonstrated that exposure to 15 ppm NO 2 increased the expression of allergically inflamed mice (Martin et al, 2013). Similarly, excessive mucus production by hyperplastic goblet cells was reported in patients with acute and chronic asthma (Ordonez et al, 2001).…”