Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC).
Duffy antigen/receptor for chemokines (DARC) is a promiscuous receptor for chemokines that is required for Plasmodium vivax infection of erythroid cells. This receptor is expressed by subsets of endothelial, as well as erythroid cells. Selection for protection from malaria infection resulted in an erythroid-specific defect, suggesting that DARC may play a critical role in endothelial biology. Mice with targeted disruption of this gene were generated, and the function of DARC in inflammation was explored. RNA from spleens of homozygous mutant mice lacked DARC transcripts, which were abundant in wild-type (+/+) and heterozygote (+/-) mice. DARC(-/-) mice lacked developmental abnormalities and were healthy at 1 year. Whereas hematologic parameters were within normal ranges, erythrocytes from nullizygous mice lacked CXC and CC chemokine-binding activity. Challenge with lipopolysaccharide resulted in significantly increased inflammatory infiltrates in lung and liver of nullizygous mice. These results suggest that DARC modulates the intensity of inflammatory reactions as a sink for chemokines. (Blood. 2000;96:1681-1684)
Dawson
T C
TC
Department of Pathology, University of North Carolina, Chapel Hill, NC, USA.
Lentsch
A B
AB
Wang
Z
Z
Cowhig
J E
JE
Rot
A
A
Maeda
N
N
Peiper
S C
SC
D000818:Animals; D000953:Antigens, Protozoan; D001667:Binding, Competitive / Q000187:drug effects; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D018932:Chemokine CCL2 / Q000378:metabolism; D004731:Endotoxins / Q000494:pharmacology*; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005838:Genotype; D007249:Inflammation / Q000139:chemically induced / Q000378:metabolism; D016209:Interleukin-8 / Q000378:metabolism; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides / Q000494:pharmacology; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020556:Neutrophil Infiltration / Q000187:drug effects; D009195:Peroxidase / Q000378:metabolism; D015800:Protozoan Proteins; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics* / Q000378:metabolism
D000953:Antigens, Protozoan; D002352:Carrier Proteins; D018932:Chemokine CCL2; C066001:Duffy antigen binding protein, Plasmodium; D004731:Endotoxins; D016209:Interleukin-8; D007457:Iodine Radioisotopes; D008070:Lipopolysaccharides; D015800:Protozoan Proteins; D012333:RNA, Messenger; D011956:Receptors, Cell Surface; D009195:Peroxidase