Diesel exhaust particle induction of IL-17A contributes to severe asthma

Abstract

Background: IL-17A has been implicated in severe forms of asthma. However, the factors that promote IL-17A production during the pathogenesis of severe asthma remain undefined. Diesel exhaust particles (DEPs) are a major component of traffic-related air pollution and are implicated in asthma pathogenesis and exacerbation.

Objective: We sought to determine the mechanism by which DEP exposure affects asthma severity using human and mouse studies.

Methods: BALB/c mice were challenged with DEPs with or without house dust mite (HDM) extract. Airway inflammation and function, bronchoalveolar lavage fluid cytokine levels, and flow cytometry of lung T cells were assessed. The effect of DEP exposure on the frequency of asthma symptoms and serum cytokine levels was determined in children with allergic asthma.

Results: In mice exposure to DEPs alone did not induce asthma. DEP and HDM coexposure markedly enhanced airway hyperresponsiveness compared with HDM exposure alone and generated a mixed T(H)2 and T(H)17 response, including IL-13(+)IL-17A(+) double-producing T cells. IL-17A neutralization prevented DEP-induced exacerbation of airway hyperresponsiveness. Among 235 high DEP-exposed children with allergic asthma, 32.2% had more frequent asthma symptoms over a 12-month period compared with only 14.2% in the low DEP-exposed group (P = .002). Additionally, high DEP-exposed children with allergic asthma had nearly 6 times higher serum IL-17A levels compared with low DEP-exposed children.

Conclusions: Expansion of T(H)17 cells contributes to DEP-mediated exacerbation of allergic asthma. Neutralization of IL-17A might be a useful potential therapeutic strategy to counteract the asthma-promoting effects of traffic-related air pollution, especially in highly exposed patients with severe allergic asthma.

Keywords: AHR; Airway hyperresponsiveness; Allergic asthma; BALF; Bronchoalveolar lavage fluid; DEP; Diesel exhaust particle; Forkhead box protein 3; Foxp3; GCPCR; Greater Cincinnati Pediatric Clinic Repository; HDM; House dust mite; IL-13 receptor; IL-13R; IL-17A; OR; Odds ratio; PE; PEES; Pediatric Environmental Exposures Study; Phycoerythrin; Regulatory T; SPT; Skin prick test; Treg; diesel exhaust particle; house dust mite; regulatory T cell.