Key Points This study explores a pathway that promotes Th2 cell inflammation in RV exacerbation. Inhibiting factors in this pathway could potentially benefit asthmatic patients. Rhinovirus (RV) infections in asthmatic patients are often associated with asthma exacerbation, characterized by worsened airways hyperreactivity and increased immune cell infiltration to the airways. The C-X-C chemokines, CXCL3 and CXCL5, regulate neutrophil trafficking to the lung via CXCR2, and their expression in the asthmatic lung is associated with steroid-insensitive type 2 inflammatory signatures. Currently, the role of CXCL3 and CXCL5 in regulating neutrophilic and type 2 responses in viral-induced asthma exacerbation is unknown. Inhibition of CXCL3 or CXCL5 with silencing RNAs in a mouse model of RV-induced exacerbation of asthma attenuated the accumulation of CXCR2+ neutrophils, eosinophils, and innate lymphoid cells in the lung and decreased production of type 2 regulatory factors IL-25, IL-33, IL-5, IL-13, CCL11, and CCL24. Suppression of inflammation was associated with decreased airways hyperreactivity, mucus hypersecretion, and collagen deposition. Similar results were obtained by employing RC-3095, which has been shown to bind to CXCR2, or by depletion of neutrophils. Our data demonstrate that CXCL3 and CXCL5 may be critical in the perpetuation of RV-induced exacerbation of asthma through the recruitment of CXCR2-positive neutrophils and by promoting type 2 inflammation. Targeting the CXCL3/CXCL5/CXCR2 axis may provide a new therapeutic approach to attenuating RV-induced exacerbations of asthma.

中文翻译：

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CXCL3/CXCL5/CXCR2 中性粒细胞趋化轴在鼻病毒诱导的哮喘恶化模型中调节 2 型反应中的关键作用

要点 本研究探索了促进 RV 恶化中 Th2 细胞炎症的途径。该途径中的抑制因子可能有益于哮喘患者。哮喘患者的鼻病毒 (RV) 感染通常与哮喘恶化有关，其特征是气道高反应性恶化和气道免疫细胞浸润增加。CXC 趋化因子 CXCL3 和 CXCL5 通过 CXCR2 调节中性粒细胞向肺的运输，它们在哮喘肺中的表达与类固醇不敏感的 2 型炎症特征相关。目前，CXCL3 和 CXCL5 在调节病毒诱导的哮喘恶化中的中性粒细胞和 2 型反应中的作用尚不清楚。在 RV 诱导的哮喘恶化小鼠模型中用沉默 RNA 抑制 CXCL3 或 CXCL5 减弱了 CXCR2+ 中性粒细胞、嗜酸性粒细胞和先天淋巴细胞在肺中的积累，并减少了 2 型调节因子 IL-25、IL-33 的产生、IL-5、IL-13、CCL11 和 CCL24。炎症的抑制与气道高反应性、粘液分泌过多和胶原沉积减少有关。通过使用 RC-3095 获得了类似的结果，该 RC-3095 已被证明与 CXCR2 结合，或通过中性粒细胞的消耗获得。我们的数据表明，CXCL3 和 CXCL5 可能通过募集 CXCR2 阳性中性粒细胞和促进 2 型炎症，在维持 RV 诱导的哮喘恶化中起关键作用。