Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease
Cleavage of CXCR1 on neutrophils disables bacterial killing in cystic fibrosis lung disease
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DOI：
10.1038/nm1690
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发表时间：
2007-12-01
期刊：
影响因子：
82.9
通讯作者：
Griese, Matthias
中科院分区：
文献类型：
--
作者：
Hartl, Dominik;Latzin, Philipp;Griese, Matthias
白介素8(IL-8)通过趋化因子受体CXCR1和CXCR2激活中性粒细胞。然而，囊性纤维化患者的呼吸道经常被细菌病原体定植，尽管存在大量的中性粒细胞和IL-8。在这里，我们表明，IL-8通过CXCR1而不是CXCR2促进中性粒细胞对细菌的杀灭。囊性纤维化患者呼吸道中的非竞争性蛋白分解活性会切割中性粒细胞上的CXCR1，并使其丧失杀菌能力。这些影响是依赖于蛋白酶浓度的，在慢性阻塞性肺疾病患者中也有较小程度的发生。受体裂解通过Toll样受体2诱导糖基化的CXCR1片段的释放，这些片段能够刺激哮喘上皮细胞产生IL-8。在体内，吸入α1抗胰蛋白酶抑制了CXCR1的表达，并改善了囊性纤维化患者的杀菌效果。CXCR1的裂解及其功能后果，以及作为生物活性成分的可溶性CXCR1片段的鉴定，代表了囊性纤维化和其他慢性肺部疾病的新的病理生理机制。
Interleukin-8 (IL-8) activates neutrophils via the chemokine receptors CXCR1 and CXCR2. However, the airways of individuals with cystic fibrosis are frequently colonized by bacterial pathogens, despite the presence of large numbers of neutrophils and IL-8. Here we show that IL-8 promotes bacterial killing by neutrophils through CXCR1 but not CXCR2. Unopposed proteolytic activity in the airways of individuals with cystic fibrosis cleaved CXCR1 on neutrophils and disabled their bacterial-killing capacity. These effects were protease concentration-dependent and also occurred to a lesser extent in individuals with chronic obstructive pulmonary disease. Receptor cleavage induced the release of glycosylated CXCR1 fragments that were capable of stimulating IL-8 production in bronchial epithelial cells via Toll-like receptor 2. In vivo inhibition of proteases by inhalation of alpha 1-antitrypsin restored CXCR1 expression and improved bacterial killing in individuals with cystic fibrosis. The cleavage of CXCR1, the functional consequences of its cleavage, and the identification of soluble CXCR1 fragments that behave as bioactive components represent a new pathophysiologic mechanism in cystic fibrosis and other chronic lung diseases.