Hartl Dominik, Latzin Philipp, Hordijk Peter, Marcos Veronica, Rudolph Carsten, Woischnik Markus, Krauss-Etschmann Susanne, Koller Barbara, Reinhardt Dietrich, Roscher Adelbert A, Roos Dirk, Griese Matthias
Children's Hospital Research Center, Ludwig-Maximilians University, Munich 80337, Germany.
Nat Med. 2007 Dec;13(12):1423-30. doi: 10.1038/nm1690. Epub 2007 Dec 2.
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 alpha1-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.
白细胞介素-8（IL-8）通过趋化因子受体CXCR1和CXCR2激活中性粒细胞。然而，尽管存在大量中性粒细胞和IL-8，但囊性纤维化患者的气道仍常被细菌病原体定植。在此我们表明，IL-8通过CXCR1而非CXCR2促进中性粒细胞对细菌的杀伤。囊性纤维化患者气道中不受抑制的蛋白水解活性可切割中性粒细胞上的CXCR1并使其细菌杀伤能力丧失。这些作用呈蛋白酶浓度依赖性，在慢性阻塞性肺疾病患者中也有较小程度的发生。受体切割诱导糖基化CXCR1片段的释放，这些片段能够通过Toll样受体2刺激支气管上皮细胞产生IL-8。通过吸入α1-抗胰蛋白酶在体内抑制蛋白酶可恢复CXCR1表达，并改善囊性纤维化患者的细菌杀伤能力。CXCR1的切割、其切割的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中的一种新的病理生理机制。
