Exaggerated response to endotoxin in mice lacking the Duffy antigen/receptor for chemokines (DARC)

Abstract

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.

Analysis of gene and protein expression in healthy and carious tooth pulp with cDNA microarray and two‐dimensional gel electrophoresis

“…The best-known effect of MSP is chemoattraction and activation of macrophages (36). The main role of DARC occurs during pathological inflammatory responses, as a scavenger on the red blood cell surface to eliminate excess toxic chemokines produced in response to bacterial toxins, such as lipopolysaccharide (37). OSM is a powerful and selective polymorphonuclear monocyte recruiter at the site of inflammation, which may be important in more prolonged inflammatory conditions (38), such as pulpitis.…”

International Union of Basic and Clinical Pharmacology. LXXXIX. Update on the Extended Family of Chemokine Receptors and Introducing a New Nomenclature for Atypical Chemokine Receptors

“…ACKR1 plays diverse pathophysiological roles in chemokine homeostasis, largely dependent on its cellular expression site. Erythrocyte ACKR1 was traditionally considered to act as a chemokine "sink," dampening the levels of circulating inflammatory chemokines, thus suppressing systemic leukocyte activation (Darbonne et al, 1991;Neote et al, 1993;Dawson et al, 2000b;Reutershan et al, 2009). Curiously, erythrocyte ACKR1 also maintains chemokine levels in blood, not only on the erythrocyte surface, but also in plasma, both in normal conditions and during inflammation, although the latter finding was not observed by all investigators (Jilma-Stohlawetz et al, 2001;Fukuma et al, 2003;Lee et al, 2006;Mayr et al, 2008).…”

Syndecans in inflammation

“…Data by M. Götte and M. Bernfield. can-1 knockout mice appear to be strikingly dissimilar to mouse models of leukocyte adhesion deficiencies (LAD), which carry mutations in adhesion molecules like e.g., selectins or leukocyte integrin subunits (138). Whereas defects in molecules causing LAD often lead to decreased inflammatory responses, mice lacking the Duffy antigen/receptor for chemokines (DARC) display increased inflammatory reactions after LPS stimulation, and thus show a phenotype more similar to the sdc1 Ϫ/Ϫ mouse (139). DARC is expressed on endothelium and erythrocytes, and binds promiscuously to CC and CXC chemokines, like HS (140).…”

“…DARC is expressed on endothelium and erythrocytes, and binds promiscuously to CC and CXC chemokines, like HS (140). The inflammatory responses in DARC-deficient mice suggests that this molecule could sequester chemokines and prevent them from activating leukocytes (139). Similar mechanisms might play a role in the inflammatory response of sdc1 Ϫ/Ϫ mice.…”