Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation.
Molecular Mechanisms of Airway Hyperresponsiveness in a Murine Model of Steroid-Resistant Airway Inflammation.
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DOI：
10.4049/jimmunol.1501531
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发表时间：
2016-02-01
期刊：
影响因子：
--
通讯作者：
Alcorn JF
中科院分区：
文献类型：
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作者：
Manni ML;Mandalapu S;McHugh KJ;Elloso MM;Dudas PL;Alcorn JF
IL-13和IL-17A分别主要由Th2和Th17细胞产生，在哮喘发病中起重要作用。我们研究了IL-13和IL-17A在哮喘双Th2/Th17模型中介导气道高反应性（AHR）、肺部炎症和粘液化生中的作用。用单克隆抗体中和IL-13和/或IL-17A。Th2/Th17过过性转移诱导混合哮喘表型，其特征是嗜酸性粒细胞和中性粒细胞升高、组织炎症、粘液化生和AHR，这些在类固醇治疗下部分可逆。IL-13和/或IL-17A的中和在很大程度上不影响肺部炎症和准静态肺顺应性。然而，单独中和IL-13或联合IL-17A能够显著减轻AHR和粘液化生。此外，在IL-13和IL-13/IL-17A抗体治疗后，STAT6的激活减弱。接下来，我们使用STAT6−/−小鼠评估STAT6在Th2/ th17介导的过敏性气道疾病中的作用。与对照组相比，过继转染Th2/Th17细胞的STAT6−/−小鼠AHR降低。这些数据表明，IL-13以STAT6依赖的方式驱动AHR和粘液化生，而不直接导致气道或组织炎症。在Th2/Th17混合模型中，IL-17A独立参与AHR，但仅部分介导炎症和粘液化生。
IL-13 and IL-17A, produced mainly by Th2 and Th17 cells respectively, have an influential role in asthma pathogenesis. We examined the role of IL-13 and IL-17A in mediating airway hyperresponsiveness (AHR), lung inflammation, and mucus metaplasia in a dual Th2/Th17 model of asthma. IL-13 and/or IL-17A were neutralized using monoclonal antibodies. Th2/Th17 adoptive transfer induced a mixed asthma phenotype characterized by elevated eosinophilia and neutrophilia, tissue inflammation, mucus metaplasia, and AHR that were partially reversible with steroid treatment. Pulmonary inflammation and quasi-static lung compliance were largely unaffected by neutralization of IL-13 and/or IL-17A. However, neutralization of IL-13 alone or in combination with IL-17A was able to significantly attenuate AHR and mucus metaplasia. Further, STAT6 activation was attenuated following IL-13 and IL-13/IL-17A antibody treatment. We next assessed the role of STAT6 in Th2/Th17-mediated allergic airway disease using STAT6−/− mice. STAT6−/− mice adoptively transferred with Th2/Th17 cells had decreased AHR when compared to controls. These data suggest that IL-13 drives AHR and mucus metaplasia in a STAT6 dependent manner, without directly contributing to airway or tissue inflammation. IL-17A independently contributes to AHR, but only partially mediates inflammation and mucus metaplasia in a mixed Th2/Th17 model of steroid-resistant asthma.