title: Expression of MIG/CXCL9 in cystic fibrosis and modulation of its activities by elastase of Pseudomonas aeruginosa.
abstract: In cystic fibrosis (CF), colonization of the airways with Pseudomonas aeruginosa is associated with disease deterioration. The mechanism behind the disease progression is not fully understood. The present work shows that the antibacterial chemokine MIG/CXCL9 is present in the airways and in sputum of CF patients. MIG/CXCL9 showed high bactericidal activity against. P. aeruginosa, including some strains from the airways of CF patients. Full-length MIG/CXCL9 was detected in sputum from healthy controls and CF patients colonized with P. aeruginosa. However, degraded MIG/CXCL9 was only found in CF sputum. In vitro, elastase of P. aeruginosa cleaved off a fragment of similar size and two additional fragments from MIG/CXCL9. The fragments showed less bactericidal activity against P. aeruginosa compared with the full-length protein. The fragments did not activate the MIG/CXCL9 receptor CXCR3 (expressed e.g. by NK cells, mast cells, and activated T cells) but instead displayed noncompetitive inhibition. In vitro, a decrease in CXCR3-bearing cells was found within and in the proximity of the bronchial epithelium of CF lung tissue compared with controls. Taken together, both bactericidal and cell-recruiting activities of MIG/CXCL9 are corrupted by P. aeruginosa through release of elastase, and this may contribute to impaired airway host defense in CF.
authors.affiliation: Sections for Respiratory Medicine and Allergology, Department of Clinical Sciences, Lund University, Lund, Sweden.
authors.forename: Sandra
authors.initials: S
authors.lastname: Jovic
authors.forename: Medya
authors.initials: M
authors.lastname: Shikhagaie
authors.forename: Matthias
authors.initials: M
authors.lastname: Mörgelin
authors.forename: Sven
authors.initials: S
authors.lastname: Kjellström
authors.forename: Jonas
authors.initials: J
authors.lastname: Erjefalt
authors.forename: Anders I
authors.initials: AI
authors.lastname: Olin
authors.forename: Inga-Maria
authors.initials: IM
authors.lastname: Frick
authors.forename: Arne
authors.initials: A
authors.lastname: Egesten
mesh_terms: D001426:Bacterial Proteins / Q000276:immunology* / Q000378:metabolism; D054370:Chemokine CXCL9 / Q000276:immunology* / Q000378:metabolism; D003550:Cystic Fibrosis / Q000201:enzymology / Q000276:immunology* / Q000382:microbiology / Q000473:pathology; D005260:Female; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000276:immunology* / Q000378:metabolism; D059748:Proteolysis; D011550:Pseudomonas aeruginosa / Q000201:enzymology / Q000276:immunology*; D054367:Receptors, CXCR3 / Q000276:immunology* / Q000378:metabolism; D013183:Sputum / Q000276:immunology / Q000382:microbiology
chemical_list: D001426:Bacterial Proteins; C080810:CXCL9 protein, human; C515187:CXCR3 protein, human; D054370:Chemokine CXCL9; D054367:Receptors, CXCR3; D008666:Metalloendopeptidases; C043859:pseudolysin, Pseudomonas aeruginosa