Journal
JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
Volume 142, Issue 3, Pages 942-958Publisher
MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2017.11.044
Keywords
Ozone; ST2; IL-33; AHR; E-cadherin; inflammation; neutrophils
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Funding
- Centre National de la Recherche Scientifique (CNRS)
- French Institute of Health and Medical Research (INSERM)
- European Regional Development Fund (FEDER) [2016-00110366]
- la Region Centre (Respir_Ozone) [2014-00091905]
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Background: IL-33 plays a critical role in regulation of tissue homeostasis, injury, and repair. Whether IL-33 regulates neutrophil recruitment and functions independently of airways hyperresponsiveness (AHR) in the setting of ozone-induced lung injury and inflammation is unclear. Objective: We sought to examine the role of the IL-33/ST2 axis in lung inflammation on acute ozone exposure in mice. Methods: ST2- and 1133 deficient, IL-33 citrine reporter, and C57BL/6 (wild-type) mice underwent a single ozone exposure (1 ppm for 1 hour) in all studies. Cell recruitment in lung tissue and the bronchoalveolar space, inflammatory parameters, epithelial barrier damage, and airway hyperresponsiveness (AHR) were determined. Results: We report that a single ozone exposure causes rapid disruption of the epithelial barrier within 1 hour, followed by a second phase of respiratory barrier injury with increased neutrophil recruitment, reactive oxygen species production, AHR, and IL-33 expression in epithelial and myeloid cells in wild-type mice. In the absence of IL-33 or IL-33 receptor/ST2, epithelial cell injury with protein leak and myeloid cell recruitment and inflammation are further increased, whereas the tight junction proteins E-cadherin and zonula occludens 1 and reactive oxygen species expression in neutrophils and AHR are diminished. ST2 neutralization recapitulated the enhanced ozone-induced neutrophilic inflammation. However, myeloid cell depletion using GR-1 antibody reduced ozone-induced lung inflammation, epithelial cell injury, and protein leak, whereas administration of recombinant mouse IL-33 reduced neutrophil recruitment in 1133 deficient mice. Conclusion: Data demonstrate that ozone causes an immediate barrier injury that precedes myeloid cell mediated inflammatory injury under the control of the IL-33/ST2 axis. Thus IL-33/ST2 signaling is critical for maintenance of intact epithelial barrier and inflammation.
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