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* Childrens’ Hospital and
Institute of Pathology, Ludwig-Maximilians-University, Munich, Germany;
Clinical Cooperation Group "Pediatric Immune Regulation" and
Comprehensive Pneumology Center, Helmholtz Center Munich, German Research Center for Environmental Health, Munich, Germany;
¶ Sanquin Research and Landsteiner Laboratory and
|| Emma Children’s Hospital, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands; and
# Paediatric Department, Respiratory and Allergic Disease Division, Medical University of Graz, Austria
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.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 Address correspondence and reprint requests to Dr. Dominik Hartl, Childrens’ Hospital, Ludwig-Maximilians-University, Lindwurmstrasse 2a, D-80337 Munich, Germany. E-mail address: dhartl{at}med.uni-muenchen.de
2 Abbreviations used in this paper: BALF, bronchoalveolar lavage fluid; SF, synovial fluid; RA, rheumatoid arthritis; PAF, platelet-activating factor; CHX. cycloheximide; LTA, lipoteichoic acid; poly(I:C), polyinosine-polycytidylic acid; PGN, peptidoglycan; MDP, muranyl peptide; Pam3CSK4, Pam3CysSerLys4; CF, cystic fibrosis; COPD, cystic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 s; MFI, mean fluorescence intensity; PI, propidium iodide; FSC, forward scatter; SSC, side scatter; LY, Lucifer Yellow; DHR, dihydrorhodamine 123; CytB, cytochalasin B.
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