IL-17A Modulates Oxidant Stress-Induced Airway Hyperresponsiveness but Not Emphysema

Mariona Pinart,Kian Fan Chung,Feng Li,Jie Zhu,Farhana Hussain,Min Zhang,Bernard Ryffel,Coen Wiegman,Chuen-Mao Yang

doi:10.1371/journal.pone.0058452

Abstract

IL-17A induces the release of pro-inflammatory cytokines and of reactive oxygen species which could lead to neutrophilic inflammation. We determined the role of IL-17 receptor (IL-17R) signalling in oxidant-induced lung emphysema and airway hyperresponsiveness. IL-17R−/− and wild-type C57/BL6 mice were exposed to ozone (3 ppm; 3 hours) for 12 times over 6 weeks. Bronchial responsiveness to acetylcholine was measured, and lungs were retrieved. Mean linear intercept (Lm) and isometric contractile responses of intrapulmonary airways to acetylcholine were determined. In wild-type mice but not in IL-17R−/−, chronic ozone exposure caused airway hyperresponsiveness. The increase in Lm after chronic ozone exposure of wild-type mice was also observed in IL-17R−/− mice. The increased maximal contractile response to acetylcholine seen in airways of wild-type mice exposed to ozone was abolished in IL-17R−/− mice. p38-mitogen-activated protein kinase (MAPK) and dexamethasone-dependent increase in contractile response was reduced in airways from IL-17R−/− ozone-exposed mice. Lung inflammation scores were not altered in IL-17R−/− mice exposed to ozone compared to wild-type mice. The increased release of IL-17 and IL-1β, and the activation of p38 MAPK in the lungs of ozone-exposed mice was reduced in IL-17R−/− mice. IL-17R signalling underlies the increase in airway hyperresponsiveness seen after ozone exposure, mediated by the increased contractility of airway smooth muscle. The emphysema and lung inflammation induced by ozone is not dependent on IL-17.

Highlights

Cigarette smoking is the most commonly encountered risk factor for chronic obstructive pulmonary disease (COPD) and is a potent inducer of oxidative stress, which plays an important role in the pathogenesis of COPD by activating pathways that lead to chronic inflammation and emphysema as demonstrated in mouse models of cigarette exposure [1,2]
IL-17R2/2 mice exposed to ozone did not exhibit Airway hyperresponsiveness (AHR) to ACh compared with IL17R2/2 air-exposed mice (–logPC100 ozone: 21.71360.086 vs air: 21.72260.160; Fig. 1)
We have shown that repeated exposure to ozone induces lung emphysema and inflammation as previously reported, and in this study, we demonstrated an increase in airway responsiveness to acetylcholine, accompanied by an ex-vivo increase in the maximal isometric contractile response to acetylcholine

Summary

Introduction

Cigarette smoking is the most commonly encountered risk factor for chronic obstructive pulmonary disease (COPD) and is a potent inducer of oxidative stress, which plays an important role in the pathogenesis of COPD by activating pathways that lead to chronic inflammation and emphysema as demonstrated in mouse models of cigarette exposure [1,2]. Exposure to ozone increases the contractility of the airways and causes bronchial hyperrresponsiveness to constrictor agents such as acetylcholine [5]. IL-17A induces the release of the pro-inflammatory cytokines, CXCL-8, CXCL1 (GRO-a), KC, GCSF and GM-CSF from airway epithelial cells, smooth muscle cells and macrophages, and thereby orchestrates neutrophilic inflammation and release of reactive oxygen species [6,8]

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Conclusion