title: The neutrophil-recruiting chemokine GCP-2/CXCL6 is expressed in cystic fibrosis airways and retains its functional properties after binding to extracellular DNA.
abstract: 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.
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Jovic
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: H M
authors.initials: HM
authors.lastname: Linge
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: M M
authors.initials: MM
authors.lastname: Shikhagaie
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: A I
authors.initials: AI
authors.lastname: Olin
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: L
authors.initials: L
authors.lastname: Lannefors
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: J S
authors.initials: JS
authors.lastname: Erjefält
authors.affiliation: Division of Infection Medicine, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: M
authors.initials: M
authors.lastname: Mörgelin
authors.affiliation: Division of Respiratory Medicine and Allergology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Egesten
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D016022:Case-Control Studies; D003550:Cystic Fibrosis / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D004247:DNA / Q000276:immunology* / Q000378:metabolism; D065206:Extracellular Traps / Q000737:chemistry / Q000276:immunology*; D015870:Gene Expression; D006801:Humans; D019272:Leukocyte Elastase / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D018375:Neutrophil Activation; D020556:Neutrophil Infiltration; D009504:Neutrophils / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D011485:Protein Binding; D059748:Proteolysis; D011550:Pseudomonas aeruginosa / Q000201:enzymology; D012137:Respiratory System / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D013045:Species Specificity; D013183:Sputum / Q000737:chemistry / Q000276:immunology
chemical_list: D001426:Bacterial Proteins; D004247:DNA; D019272:Leukocyte Elastase