DARC on RBC limits lung injury by balancing compartmental distribution of CXC chemokines.
The Duffy antigen receptor for chemokines (DARC) has a high affinity for CC and CXC chemokines. However, it lacks the ability to induce cell responses that are typical for classical chemokine receptors. The role of DARC in inflammatory conditions remains to be elucidated. We studied the role of DARC in a murine model of acute lung injury. We found that in Darc-gene-deficient (Darc(-/-)) mice, LPS-induced PMN migration into the alveolar space was elevated more than twofold. In contrast, PMN adhesion to endothelial cells and within the interstitial space was reduced in Darc(-/-) mice. Darc(-/-) mice also exhibited increased microvascular permeability. Elevated PMN migration in Darc(-/-) mice was associated with increased concentrations of two essential CXCR2 ligands, CXCL1 and CXCL2/3 in the alveolar space. In the blood, CXCL1 was mostly associated with RBC in WT mice and with plasma in Darc(-/-) mice. We found that DARC on RBC prevented excessive PMN migration into the alveolar space. In contrast, DARC on non-hematopoietic cells appeared to have only minor effects on leukocyte trafficking in this model. These findings show how DARC regulates lung inflammation by controlling the distribution and presentation of chemokines that bind CXCR2.
Reutershan
Jörg
J
Department of Anesthesiology and Intensive Care Medicine, University of Tübingen, Tübingen, Germany. joerg.reutershan@uni-tuebingen.de
Harry
Brian
B
Chang
Daniel
D
Bagby
Gregory J
GJ
Ley
Klaus
K
D000818:Animals; D008297:Male; D051379:Mice; D055371:Acute Lung Injury / Q000378:metabolism / Q000473:pathology; D000280:Administration, Inhalation; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D002199:Capillary Permeability / Q000187:drug effects / Q000235:genetics; D002465:Cell Movement / Q000235:genetics; D054360:Chemokine CXCL1 / Q000032:analysis / Q000097:blood / Q000378:metabolism; D054426:Chemokine CXCL2 / Q000032:analysis / Q000097:blood / Q000378:metabolism; D019743:Chemokines, CXC / Q000378:metabolism; D002678:Chimera / Q000502:physiology; D004195:Disease Models, Animal; D004375:Duffy Blood-Group System / Q000502:physiology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism; D004912:Erythrocytes / Q000378:metabolism; D008070:Lipopolysaccharides / Q000008:administration & dosage / Q000494:pharmacology; D008168:Lung / Q000378:metabolism / Q000473:pathology; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000166:cytology / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000502:physiology
D054360:Chemokine CXCL1; D054426:Chemokine CXCL2; D019743:Chemokines, CXC; C475895:Cxcl1 protein, mouse; C404915:Cxcl2 protein, mouse; D004375:Duffy Blood-Group System; D008070:Lipopolysaccharides; D011956:Receptors, Cell Surface; C483025:Ackr1 protein mouse