CXCL5 Regulates Chemokine Scavenging and Pulmonary Host Defense to Bacterial Infection

• Published in: Immunity (Cambridge, Mass.) Mass.), 2010-07, Vol.33 (1), p.106-117
• Main Authors: Mei, Junjie, Liu, Yuhong, Dai, Ning, Favara, Michael, Greene, Teshell, Jeyaseelan, Samithamby, Poncz, Mortimer, Lee, Janet S., Worthen, G. Scott
• Format: Article
• Language: English
• Subjects: Animals; Bacterial infections; Binding sites; Blood Platelets - metabolism; Blood Platelets - pathology; Cell Movement - genetics; CELLIMMUNO; Chemokine CXCL1 - blood; Chemokine CXCL2 - blood; Chemokine CXCL5 - genetics; Chemokine CXCL5 - immunology; Chemokine CXCL5 - metabolism; Chemokines; Colony Count, Microbial; Competition; Duffy Blood-Group System - metabolism; E coli; Erythrocytes - metabolism; Erythrocytes - pathology; Escherichia coli - growth & development; Escherichia coli - immunology; Escherichia coli Infections - blood; Escherichia coli Infections - complications; Escherichia coli Infections - genetics; Escherichia coli Infections - immunology; Heparan Sulfate Proteoglycans - metabolism; Homeostasis; Leukocytes; Lung - metabolism; Lung - pathology; Mice; Mice, Knockout; MOLIMMUNO; Mortality; Neutrophils - metabolism; Neutrophils - pathology; Plasma; Pneumonia; Pneumonia - blood; Pneumonia - etiology; Pneumonia - genetics; Pneumonia - immunology; Protein Binding - genetics; Receptors, Cell Surface - metabolism; Rodents
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2010.07.009

The chemokine sink hypothesis pertaining to erythrocyte Duffy Antigen Receptor for Chemokines (DARC) during inflammation has received considerable attention, but lacks direct in vivo evidence. Here we demonstrate, using mice with a targeted deletion in CXCL5, that CXCL5 bound erythrocyte DARC and impaired its chemokine scavenging in blood. CXCL5 increased the plasma concentrations of CXCL1 and CXCL2 in part through inhibiting chemokine scavenging, impairing chemokine gradients and desensitizing CXCR2, which led to decreased neutrophil influx to the lung, increased lung bacterial burden and mortality in an Escherichia coli pneumonia model. In contrast, CXCL5 exerted a predominant role in mediating neutrophil influx to the lung during inflammation after LPS inhalation. Platelets and lung resident cells were the sources of homeostatic CXCL5 in blood and inflammatory CXCL5 in the lung respectively. This study presents a paradigm whereby platelets and red cells alter chemokine scavenging and neutrophil-chemokine interaction during inflammation. ► The chemokine CXCL5 elevates CXCL1 and CXCL2 concentrations in plasma ► CXCL5 blocks Duffy antigen and Heparan Sulfate Proteoglycan chemokine scavenging ► Elevated concentrations of CXCL1 and CXCL2 impair chemokine gradient formation ► Altered chemokine gradients impair neutrophil trafficking and bacterial clearance