The Duffy antigen modifies systemic and local tissue chemokine responses following lipopolysaccharide stimulation.
The Duffy blood group Ag (dfy) binds selective CXC and CC chemokines at high affinity and is expressed on erythrocytes and endothelial cells. However, it does not transmit a signal via G proteins, as occurs with other seven-transmembrane receptors. We hypothesized that dfy functions as a chemokine reservoir and regulates inflammation by altering soluble chemokine concentrations in the blood and tissue compartments. We determined whether Duffy Ag "loss-of-function" phenotypes (human and murine) are associated with alterations in plasma chemokine concentrations during the innate inflammatory response to LPS. Plasma CXCL8 and CCL2 concentrations from humans homozygous for the GATA-1 box polymorphism, a dfy polymorphism that abrogates erythrocyte chemokine binding, were higher than in heterozygotes following LPS stimulation of their whole blood in vitro. Similarly, dfy(-/-) mice showed higher plasma MIP-2 concentrations than dfy(+/+) mice following LPS stimulation of whole blood in vitro. We then determined the relative contributions of erythrocyte and endothelial Duffy Ag in modifying chemokine concentrations and neutrophil recruitment in the lungs following intratracheal LPS administration in dfy(-/-) and dfy(+/+) mice reconstituted with dfy(-/-) or dfy(+/+) marrow. Mice lacking endothelial dfy expression had higher MIP-2 and keratinocyte chemoattractant concentrations in the airspaces. Mice lacking erythrocyte dfy had higher MIP-2 and keratinocyte chemoattractant concentrations in the lung tissue vascular space, but lower plasma chemokine concentrations associated with attenuated neutrophil recruitment into the airspaces. These data indicate that dfy alters soluble chemokine concentrations in blood and local tissue compartments and enhances systemic bioavailability of chemokines produced during local tissue inflammation.
Lee
Janet S
JS
Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, 3459 Fifth Avenue, Pittsburgh, PA 15213, USA. leejs3@upmc.edu
Wurfel
Mark M
MM
Matute-Bello
Gustavo
G
Frevert
Charles W
CW
Rosengart
Matthew R
MR
Ranganathan
Mrunalini
M
Wong
Venus W
VW
Holden
Tarah
T
Sutlief
Steve
S
Richmond
Ann
A
Peiper
Stephen
S
Martin
Thomas R
TR
D000293:Adolescent; D019264:Adoptive Transfer; D000328:Adult; D000368:Aged; D000818:Animals; D018932:Chemokine CCL2 / Q000097:blood; D054426:Chemokine CXCL2; D018925:Chemokines / Q000032:analysis*; D004375:Duffy Blood-Group System / Q000235:genetics* / Q000276:immunology*; D050982:GATA1 Transcription Factor / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000139:chemically induced / Q000235:genetics* / Q000276:immunology; D016209:Interleukin-8 / Q000097:blood; D008070:Lipopolysaccharides / Q000276:immunology*; D008168:Lung / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D015846:Monokines / Q000378:metabolism; D020556:Neutrophil Infiltration / Q000235:genetics / Q000276:immunology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction
D018932:Chemokine CCL2; D054426:Chemokine CXCL2; D018925:Chemokines; D004375:Duffy Blood-Group System; D050982:GATA1 Transcription Factor; C494688:GATA1 protein, human; D016209:Interleukin-8; D008070:Lipopolysaccharides; D015846:Monokines