CXCL5 regulates chemokine scavenging and pulmonary host defense to bacterial infection.
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.
Mei
Junjie
J
Division of Neonatology, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA. meij@email.chop.edu
Liu
Yuhong
Y
Dai
Ning
N
Favara
Michael
M
Greene
Teshell
T
Jeyaseelan
Samithamby
S
Poncz
Mortimer
M
Lee
Janet S
JS
Worthen
G Scott
GS
D000818:Animals; D051379:Mice; D001792:Blood Platelets / Q000378:metabolism / Q000473:pathology; D002465:Cell Movement / Q000235:genetics; D054360:Chemokine CXCL1 / Q000097:blood; D054426:Chemokine CXCL2 / Q000097:blood; D054365:Chemokine CXCL5 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015169:Colony Count, Microbial; D004375:Duffy Blood-Group System / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism / Q000473:pathology; D004926:Escherichia coli / Q000254:growth & development / Q000276:immunology; D004927:Escherichia coli Infections / Q000097:blood / Q000150:complications / Q000235:genetics / Q000276:immunology; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology; D011014:Pneumonia / Q000097:blood / Q000209:etiology / Q000235:genetics / Q000276:immunology; D011485:Protein Binding / Q000235:genetics; D011956:Receptors, Cell Surface / Q000378:metabolism
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D054365:Chemokine CXCL5; D004375:Duffy Blood-Group System; D019812:Heparan Sulfate Proteoglycans; D011956:Receptors, Cell Surface; C483025:Ackr1 protein mouse