Mathews Joel A, Krishnamoorthy Nandini, Kasahara David Itiro, Cho Youngji, Wurmbrand Allison Patricia, Ribeiro Luiza, Smith Dirk, Umetsu Dale, Levy Bruce D, Shore Stephanie Ann
Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
Environ Health Perspect. 2017 Feb;125(2):246-253. doi: 10.1289/EHP272. Epub 2016 Jul 29.
Ozone increases IL-33 in the lungs, and obesity augments the pulmonary effects of acute ozone exposure.
We assessed the role of IL-33 in the augmented effects of ozone observed in obese mice.
Lean wildtype and obese db/db mice were pretreated with antibodies blocking the IL-33 receptor, ST2, and then exposed to ozone (2 ppm for 3 hr). Airway responsiveness was assessed, bronchoalveolar lavage (BAL) was performed, and lung cells harvested for flow cytometry 24 hr later. Effects of ozone were also assessed in obese and lean mice deficient in γδ T cells and their wildtype controls.
Ozone caused greater increases in BAL IL-33, neutrophils, and airway responsiveness in obese than lean mice. Anti-ST2 reduced ozone-induced airway hyperresponsiveness and inflammation in obese mice but had no effect in lean mice. Obesity also augmented ozone-induced increases in BAL CXCL1 and IL-6, and in BAL type 2 cytokines, whereas anti-ST2 treatment reduced these cytokines. In obese mice, ozone increased lung IL-13+ innate lymphoid cells type 2 (ILC2) and IL-13+ γδ T cells. Ozone increased ST2+ γδ T cells, indicating that these cells can be targets of IL-33, and γδ T cell deficiency reduced obesity-related increases in the response to ozone, including increases in type 2 cytokines.
Our data indicate that IL-33 contributes to augmented responses to ozone in obese mice. Obesity and ozone also interacted to promote type 2 cytokine production in γδ T cells and ILC2 in the lungs, which may contribute to the observed effects of IL-33. Citation: Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246-253; http://dx.doi.org/10.1289/EHP272.
臭氧可增加肺部白细胞介素-33（IL-33）水平，肥胖会增强急性臭氧暴露对肺部的影响。
我们评估了IL-33在肥胖小鼠中观察到的臭氧增强效应中的作用。
对瘦的野生型和肥胖的db/db小鼠预先用阻断IL-33受体ST2的抗体进行处理，然后暴露于臭氧（2 ppm，持续3小时）。24小时后评估气道反应性，进行支气管肺泡灌洗（BAL），并收集肺细胞用于流式细胞术分析。还在缺乏γδT细胞的肥胖和瘦小鼠及其野生型对照中评估了臭氧的作用。
与瘦小鼠相比，臭氧使肥胖小鼠BAL中的IL-33、中性粒细胞和气道反应性增加得更多。抗ST2抗体可降低肥胖小鼠中臭氧诱导的气道高反应性和炎症，但对瘦小鼠无影响。肥胖还增强了臭氧诱导的BAL中CXC趋化因子配体1（CXCL1）和白细胞介素-6（IL-6）以及BAL中2型细胞因子的增加，而抗ST2治疗可降低这些细胞因子。在肥胖小鼠中，臭氧增加了肺部白细胞介素-13+2型固有淋巴细胞（ILC2）和白细胞介素-13+γδT细胞。臭氧增加了ST2+γδT细胞，表明这些细胞可能是IL-33的作用靶点，γδT细胞缺陷减少了肥胖相关的对臭氧反应的增加，包括2型细胞因子的增加。
我们的数据表明，IL-33促成了肥胖小鼠对臭氧的增强反应。肥胖和臭氧还相互作用，促进肺部γδT细胞和ILC2中2型细胞因子的产生，这可能导致了观察到的IL-33的作用。引文：Mathews JA, Krishnamoorthy N, Kasahara DI, Cho Y, Wurmbrand AP, Ribeiro L, Smith D, Umetsu D, Levy BD, Shore SA. 2017. IL-33 drives augmented responses to ozone in obese mice. Environ Health Perspect 125:246-253; http://dx.doi.org/10.1289/EHP272.
