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 cel ls, This receptor is expressed by subsets of endothelial, as well as erythr oid cells. Selection for protection from malaria infection resulted in an e rythroid-specific defect, suggesting that DARC may play a critical role in endothelial biology. Mice with targeted disruption of this gene were genera ted, and the function of DARC in inflammation was explored. RNA from spleen s of homozygous mutant mice lacked DARC transcripts, which were abundant in wild-type (+/+) and heterozygote (+/-) mice. DARC(-/-) mice lacked develop mental abnormalities and were healthy at 1 year. Whereas hematologic parame ters were within normal ranges, erythrocytes from nullizygous mice lacked C XC and CC chemokine-binding activity. Challenge with lipopolysaccharide res ulted in significantly increased inflammatory infiltrates in lung and liver of nullizygous mice. These results suggest that DARC modulates the intensi ty of inflammatory reactions as a sink for chemokines. (C) 2000 by The Amer ican Society of Hematology.