Critical role of CCL4 in eosinophil recruitment into the airway
Critical role of CCL4 in eosinophil recruitment into the airway
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DOI：
10.1111/cea.13382
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发表时间：
2019-06-01
影响因子：
6.1
通讯作者：
Ueki, Shigeharu
中科院分区：
文献类型：
--
作者：
Kobayashi, Yoshiki;Konno, Yasunori;Ueki, Shigeharu
背景过度的嗜酸性粒细胞在某些情况下是一种临床危重的情况。嗜酸性肺炎(EP)是一种肺部疾病，涉及肺部嗜酸性粒细胞的渗透。虽然已在EP患者的支气管肺泡灌洗液(BALF)中检测到多种趋化因子，包括嗜酸性粒细胞趋化因子-1(CCL11)、RANTES(CCL5)和巨噬细胞炎性蛋白1β(MIP-1β或CCL4)，但EP的病理生理机制，包括嗜酸性粒细胞与CCL4之间的潜在关系尚未完全阐明。结果经IL-5刺激后，纯化的人嗜酸性粒细胞主要分泌CCL4，EP患者BALF中CCL11和CCL4水平较非EP患者升高。由于与CCL11相比，CCL4水平与嗜酸性粒细胞计数和嗜酸性粒细胞颗粒蛋白表达的相关性更强，所以使用纯化的嗜酸性粒细胞进行的体外实验集中在前者的趋化因子上。有趣的是，CCl4起到了嗜酸性粒细胞的趋化作用。在小鼠模型中，给予CCL4中和抗体可减轻嗜酸粒细胞的气道渗透和气道高反应性。结论和临床关系总体而言，这些发现突出了CCL4在嗜酸性粒细胞重新聚集到呼吸道的机制中的重要作用，并可能为这一潜在的治疗靶点提供新的见解。
BackgroundExcessive eosinophil airway infiltration is a clinically critical condition in some cases. Eosinophilic pneumonia (EP) is a pulmonary condition involving eosinophil infiltration of the lungs. Although several chemokines, including eotaxin-1 (CCL11), RANTES (CCL5) and macrophage inflammatory protein 1 beta (MIP-1 beta or CCL4), have been detected in bronchoalveolar lavage fluid (BALF) from patients with EP, the pathophysiological mechanisms underlying EP, including potential relationships between eosinophils and CCL4, have not been fully elucidated.ObjectiveTo examine the involvement of CCL4 in eosinophilic airway inflammation.MethodsWe analysed supernatants of activated eosinophils and BALF from 16 patients with eosinophilic pneumonia (EP). Further, we examined the effects of CCL4 on eosinophil functions in vitro and those of anti-CCL4 neutralizing antibody in an in vivo model.ResultsWe found that purified human eosinophils stimulated with IL-5 predominantly secreted CCL4 and that patients with EP had elevated CCL11 and CCL4 levels in BALF compared with samples from individuals without EP. Because CCL4 levels were more strongly correlated with eosinophil count and expression of eosinophil granule proteins than CCL11, in vitro experiments using purified eosinophils concentrated on the former chemokine. Interestingly, CCL4 acted as a chemoattractant for eosinophils. In a mouse model, administration of a CCL4-neutralizing antibody attenuated eosinophilic airway infiltration and airway hyperresponsiveness.Conclusions and Clinical RelevanceOverall, these findings highlight an important role of CCL4 in the mechanisms underlying eosinophil recruitment into the airway and may provide a novel insight into this potential therapeutic target.