Jovic S, Linge H M, Shikhagaie M M, Olin A I, Lannefors L, Erjefält J S, Mörgelin M, Egesten A
Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Division of Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
Mucosal Immunol. 2016 Jan;9(1):112-23. doi: 10.1038/mi.2015.43. Epub 2015 May 20.
Infections in cystic fibrosis (CF), often involving Pseudomonas aeruginosa, result from a dysregulated airway immunity where one hallmark is the accumulation of necrotic and apoptotic immune cells, in particular neutrophils. In addition, neutrophils actively release DNA, forming neutrophil extracellular traps (NETs) that contain antimicrobial proteins. Altogether, free DNA in complex with actin accumulates in the airway lumen, resulting in highly viscous sputum that provides an anionic matrix, binding cationic antimicrobial proteins. In this study, granulocyte chemotactic protein 2 (GCP-2)/CXCL6, a neutrophil-activating chemokine with bactericidal properties, was detected in the airway epithelium of CF patients and was also present in azurophilic and specific granules of neutrophils. Elastase of neutrophils, but not of P. aeruginosa, completely degraded CXCL6 (chemokine (C-X-C motif) ligand 6). In addition, CXCL6 colocalized with extracellular DNA in both CF sputa and in in vitro-formed NETs. In vitro, CXCL6 bound DNA with a KD of 2,500 nM. Interestingly, both the bactericidal and the receptor-activating properties of CXCL6 (against neutrophils) remained largely unaffected in the presence of DNA. However, the chemotactic properties of CXCL6 were reduced by the presence of DNA. Taken together, CXCL6 is expressed in CF, retaining its functional properties even after binding to the anionic scaffold that extracellular DNA provides in CF.
囊性纤维化（CF）中的感染通常涉及铜绿假单胞菌，是由气道免疫失调引起的，其一个标志是坏死和凋亡免疫细胞（特别是中性粒细胞）的积累。此外，中性粒细胞会主动释放DNA，形成含有抗菌蛋白的中性粒细胞胞外陷阱（NETs）。总之，与肌动蛋白结合的游离DNA在气道腔内积聚，导致痰液高度黏稠，形成一个阴离子基质，结合阳离子抗菌蛋白。在本研究中，粒细胞趋化蛋白2（GCP-2）/CXCL6，一种具有杀菌特性的中性粒细胞激活趋化因子，在CF患者的气道上皮中被检测到，并且也存在于中性粒细胞的嗜天青颗粒和特异性颗粒中。中性粒细胞的弹性蛋白酶，而非铜绿假单胞菌的弹性蛋白酶，可完全降解CXCL6（趋化因子（C-X-C基序）配体6）。此外，在CF痰液和体外形成的NETs中，CXCL6均与细胞外DNA共定位。在体外，CXCL6以2500 nM的解离常数结合DNA。有趣的是，在存在DNA的情况下，CXCL6的杀菌特性和受体激活特性（针对中性粒细胞）基本未受影响。然而，DNA的存在会降低CXCL6的趋化特性。综上所述，CXCL6在CF中表达，即使在与CF中细胞外DNA提供的阴离子支架结合后仍保留其功能特性。
