ILC2 contribute to ozone-induced airway hyperresponsiveness in obese mice (HYP6P.266)

Abstract

Abstract Many obese asthmatics have non atopic asthma, but the mechanistic basis is poorly understood. Ozone (O3), a common air pollutant, is an asthma trigger that causes airway hyperresponsiveness (AHR) and neutrophilic inflammation. O3-induced AHR and neutrophilia are augmented in obese vs lean mice. Innate lymphoid cells type 2 (ILC2) may be driving these responses. To address this hypothesis, lean WT and obese db/db mice were exposed to room air or O3 (2 ppm) for 3 h. 24 h later, we measured AHR and performed bronchoalveolar lavage (BAL). BAL IL-5, IL-13 and IL-33 were increased by O3 in obese but not lean mice. IL-5 and IL-13 can drive AHR and are secreted by ILC2. IL-33 signaling through ST2 drives activation of ILC2. Therefore, we pretreated db/db mice with ST2 blocking antibody (provided by Dirk Smith, Amgen) prior to O3 exposure. Blocking ST2 decreased O3-induced AHR, baseline lung mechanics, neutrophilia and BAL IL-5 in db/db mice. Anti-IL-13 also decreases BAL neutrophils and lung mechanics in obese mice after O3. IL-23, IL-7, IL-22, and IL-17A were also increased by O3 in obese mice, suggesting the possible involvement of ILC3, a cell activated by IL-7 and IL-23 that secretes IL-17A and IL-22. Blocking IL-17A in a separate cohort also decreased O3 induced AHR and neutrophilia in obese mice. Taken together, our data indicate that obese mice exposed to O3 have increased activation of ILC2 and ILC3 and that these cells are driving the asthma phenotype in these mice.