Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma
Interleukin-17 orchestrates the granulocyte influx into airways after allergen inhalation in a mouse model of allergic asthma
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DOI：
10.1165/rcmb.4832
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发表时间：
2003-01-01
影响因子：
6.4
通讯作者：
Ceuppens, JL
中科院分区：
文献类型：
--
作者：
Hellings, PW;Kasran, A;Ceuppens, JL
白细胞介素 (IL)-17 由活化的记忆 CD4(+) 细胞产生，并诱导刺激中性粒细胞生成和募集的细胞因子和趋化因子。在这里，我们研究了实验性过敏性哮喘中 IL-17 在中性粒细胞支气管流入中的作用。慢性 OVA 暴露导致支气管嗜酸性粒细胞炎症的致敏小鼠吸入雾化卵清蛋白 (OVA) 会诱导发炎肺组织中早期 IL-17 mRNA 表达，同时伴有显着的支气管中性粒细胞流入。在吸入过敏原之前注射抗 IL-17 单克隆抗体 (mAb) 可强烈减少支气管中性粒细胞流入，其效果与抗炎地塞米松相同。值得注意的是，抗 IL-17 mAb 显着提高了 BAL 液和血清中的 IL-5 水平，并加剧了过敏原诱导的支气管嗜酸性粒细胞增多。在另一系列实验中，在吸入激发阶段用OVA反复给予致敏小鼠抗IL-17 mAb。该治疗方案减少了支气管中性粒细胞增多，同时减少了骨髓和血液中性粒细胞增多。此外，抗 IL-17 mAb 治疗可提高骨髓中的嗜酸性粒细胞计数和支气管 IL-5 的产生，但不会改变过敏原诱导的支气管高反应性。总之，我们的结果表明，吸入过敏原后气道中 IL-17 的表达上调，并构成了过敏原诱导的 T 细胞活化和中性粒细胞流入之间的联系。由于中性粒细胞可能在慢性严重哮喘的气道重塑中发挥重要作用，因此靶向 IL-17 可能对人类哮喘具有治疗潜力。
Interleukin (IL)-17 is produced by activated memory CD4(+) cells and induces cytokines and chemokines that stimulate neutrophil generation and recruitment. Here, we investigated the involvement of IL-17 in the bronchial influx of neutrophils in experimental allergic asthma. Inhalation of nebulized ovalbumin (OVA) by sensitized mice with bronchial eosinophilic inflammation resulting from chronic OVA exposure induced early IL-17 mRNA expression in inflamed lung tissue, concomitant with a prominent bronchial neutrophilic influx. Anti-IL-17 monoclonal antibodies (mAb) injected before allergen inhalation strongly reduced bronchial neutrophilic influx, in a manner equally as potent as the anti-inflammatory dexamethasone. Remarkably, anti-IL-17 mAb significantly enhanced IL-5 levels in both BAL fluid and serum, and aggravated allergen-induced bronchial eosinophilia. In another series of experiments, anti-IL-17 mAb were given repeatedly during the inhalatory challenge phase with OVA of sensitized mice. This treatment regimen abated bronchial neutrophilia in parallel with reduction of bone marrow and blood neutrophilia. In addition, anti-IL-17 mAb treatment elevated eosinophil counts in the bone marrow and bronchial IL-5 production, without alteration of allergen-induced bronchial hyperresponsiveness. In summary, our results demonstrate that IL-17 expression in airways is upregulated upon allergen inhalation, and constitutes the link between allergen-induced T cell activation and neutrophilic influx. Because neutrophils may be important in airway remodeling in chronic severe asthma, targeting IL-17 may hold therapeutic potential in human asthma.