Diesel exhaust particle induction of IL-17A contributes to severe asthma.
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.
Division of Asthma Research, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati, Cincinnati, Ohio.
Eric B
EB
Brandt
Melinda Butsch
MB
Kovacic
Gerald B
GB
Lee
Aaron M
AM
Gibson
Thomas H
TH
Acciani
Timothy D
TD
Le Cras
Patrick H
PH
Ryan
Alison L
AL
Budelsky
Gurjit K
GK
Khurana Hershey
D000293:Adolescent; D000485:Allergens / Q000276:immunology; D000818:Animals; D001249:Asthma / Q000209:etiology*; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000096:biosynthesis / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007249:Inflammation / Q000209:etiology; D019570:Inhalation Exposure / Q000009:adverse effects; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000097:blood; D019041:L-Selectin / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000378:metabolism; D008297:Male; D051379:Mice; D039981:Pyroglyphidae / Q000276:immunology; D012130:Respiratory Hypersensitivity / Q000209:etiology; D058504:Th17 Cells / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism; D001335:Vehicle Emissions / Q000633:toxicity
D000485:Allergens; D016207:Cytokines; D018960:Hyaluronan Receptors; D020381:Interleukin-17; D001335:Vehicle Emissions; D019041:L-Selectin
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