title: Infiltrated neutrophils acquire novel chemokine receptor expression and chemokine responsiveness in chronic inflammatory lung diseases.
abstract: Various inflammatory diseases are characterized by tissue infiltration of neutrophils. Chemokines recruit and activate leukocytes, but neutrophils are traditionally known to be restricted in their chemokine receptor (CR) expression repertoire. Neutrophils undergo phenotypic and functional changes under inflammatory conditions, but the mechanisms regulating CR expression of infiltrated neutrophils at sites of chronic inflammation are poorly defined. Here we show that infiltrated neutrophils from patients with chronic inflammatory lung diseases and rheumatoid arthritis highly express CR on their surface that are absent or only marginally expressed on circulating neutrophils, i.e., CCR1, CCR2, CCR3, CCR5, CXCR3, and CXCR4, as measured by flow cytometry, immunohistochemistry, and confocal microscopy. The induction of CR surface expression on infiltrated neutrophils was functionally relevant, because receptor activation by chemokine ligands ex vivo modulated neutrophil effector functions such as respiratory burst activity and bacterial killing. In vitro studies with isolated neutrophils demonstrated that the surface expression of CR was differentially induced in a cytokine-mediated, protein synthesis-dependent manner (CCR1, CCR3), through Toll-like (CXCR3) or NOD2 (CCR5) receptor engagement, through neutrophil apoptosis (CCR5, CXCR4), and/or via mobilization of intracellular CD63(+) granules (CXCR3). CR activation on infiltrated neutrophils may represent a key mechanism by which the local inflammatory microenvironment fine-tunes neutrophil effector functions in situ. Since the up-regulation of CR was exclusively found on infiltrated neutrophils at inflammatory sites in situ, the targeting of these G protein-coupled receptors may have the potential to site-specifically target neutrophilic inflammation.
authors.affiliation: Childrens' Hospital, Ludwig-Maximilians-University, Munich, Germany. dhartl@med.uni-muenchen.de
authors.forename: Dominik
authors.initials: D
authors.lastname: Hartl
authors.forename: Susanne
authors.initials: S
authors.lastname: Krauss-Etschmann
authors.forename: Barbara
authors.initials: B
authors.lastname: Koller
authors.forename: Peter L
authors.initials: PL
authors.lastname: Hordijk
authors.forename: Taco W
authors.initials: TW
authors.lastname: Kuijpers
authors.forename: Florian
authors.initials: F
authors.lastname: Hoffmann
authors.forename: Andreas
authors.initials: A
authors.lastname: Hector
authors.forename: Ernst
authors.initials: E
authors.lastname: Eber
authors.forename: Veronica
authors.initials: V
authors.lastname: Marcos
authors.forename: Iris
authors.initials: I
authors.lastname: Bittmann
authors.forename: Oliver
authors.initials: O
authors.lastname: Eickelberg
authors.forename: Matthias
authors.initials: M
authors.lastname: Griese
authors.forename: Dirk
authors.initials: D
authors.lastname: Roos
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000276:immunology / Q000378:metabolism; D001172:Arthritis, Rheumatoid / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D005786:Gene Expression Regulation / Q000276:immunology; D006801:Humans; D007120:Immunochemistry; D007249:Inflammation / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020556:Neutrophil Infiltration / Q000276:immunology*; D009504:Neutrophils / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D010980:Platelet Membrane Glycoproteins / Q000276:immunology / Q000378:metabolism; D011014:Pneumonia / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology*; D022142:Secretory Vesicles / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D060149:Tetraspanin 30
chemical_list: D015703:Antigens, CD; C554586:CD63 protein, human; D010980:Platelet Membrane Glycoproteins; D019707:Receptors, Chemokine; D060149:Tetraspanin 30