Cockx Maaike, Gouwy Mieke, Godding Véronique, De Boeck Kris, Van Damme Jo, Boon Mieke, Struyf Sofie
Laboratory of Molecular Immunology, Department of Microbiology and Immunology, Rega Institute for Medical Research, University of Leuven, Leuven, Belgium.
Unité de Pneumologie Pédiatrique et Mucoviscidose, Clinique Universitaire Saint-Luc UCL Brussels, Brussels, Belgium.
Front Immunol. 2017 Sep 22;8:1126. doi: 10.3389/fimmu.2017.01126. eCollection 2017.
Primary ciliary dyskinesia (PCD), cystic fibrosis (CF), and chronic obstructive airway disease are characterized by neutrophilic inflammation in the lungs. In CF and chronic obstructive airway disease, improper functioning of neutrophils has been demonstrated. We hypothesized that the pulmonary damage in PCD might be aggravated by abnormal functioning neutrophils either as a primary consequence of the PCD mutation or secondary to chronic inflammation. We analyzed chemotactic responses and chemoattractant receptor expression profiles of peripheral blood neutrophils from 36 patients with PCD, 21 healthy children and 19 healthy adults. We stimulated peripheral blood monocytes from patients and healthy controls and measured CXCL8 and IL-1β production with ELISA. PCD neutrophils displayed reduced migration toward CXCR2 ligands (CXCL5 and CXCL8) in the shape change, microchamber and microslide chemotaxis assays, whereas leukotriene B4 and complement component 5a chemotactic responses were not significantly different. The reduced response to CXCL8 was observed in all subgroups of patients with PCD (displaying either normal ultrastructure, dynein abnormalities or central pair deficiencies) and correlated with lung function. CXCR2 was downregulated in about 65% of the PCD patients, suggestive for additional mechanisms causing CXCR2 impairment. After treatment with the TLR ligands lipopolysaccharide and peptidoglycan, PCD monocytes produced more CXCL8 and IL-1β compared to controls. Moreover, PCD monocytes also responded stronger to IL-1β stimulation in terms of CXCL8 production. In conclusion, we revealed a potential link between CXCR2 and its ligand CXCL8 and the pathogenesis of PCD.
原发性纤毛运动障碍（PCD）、囊性纤维化（CF）和慢性阻塞性气道疾病的特征是肺部嗜中性粒细胞炎症。在CF和慢性阻塞性气道疾病中，已证实嗜中性粒细胞功能异常。我们推测，PCD中的肺损伤可能因嗜中性粒细胞功能异常而加重，这要么是PCD突变的主要后果，要么是慢性炎症的继发结果。我们分析了36例PCD患者、21名健康儿童和19名健康成年人外周血嗜中性粒细胞的趋化反应和趋化因子受体表达谱。我们刺激患者和健康对照的外周血单核细胞，并用酶联免疫吸附测定法测量CXCL8和IL-1β的产生。在形态改变、微孔板和微载玻片趋化试验中，PCD嗜中性粒细胞对CXCR2配体（CXCL5和CXCL8）的迁移减少，而白三烯B4和补体成分5a的趋化反应无显著差异。在所有PCD患者亚组（显示正常超微结构、动力蛋白异常或中央微管缺陷）中均观察到对CXCL8的反应降低，且与肺功能相关。约65%的PCD患者CXCR2下调，提示存在导致CXCR2受损的其他机制。在用Toll样受体配体脂多糖和肽聚糖治疗后，与对照组相比，PCD单核细胞产生更多的CXCL8和IL-1β。此外，就CXCL8产生而言，PCD单核细胞对IL-1β刺激的反应也更强。总之，我们揭示了CXCR2及其配体CXCL8与PCD发病机制之间的潜在联系。
