Chemokine homeostasis vs. chemokine presentation during severe acute lung injury: the other side of the Duffy antigen receptor for chemokines

Zarbock A, Bishop J, Muller H, Schmolke M, Buschmann K, Van Aken H, Singbartl K. Chemokine homeostasis vs. chemokine presentation during severe acute lung injury: the other side of the Duffy antigen receptor for chemokines. Am J Physiol Lung Cell Mol Physiol 298: L462-L471, 2010. First published January 8, 2010; doi:10.1152/ajplung.00224.2009.-Acute lung injury (ALI) still poses a major challenge in critical care medicine. Neutrophils, platelets, and chemokines are all considered key components in the development of ALI. The Duffy antigen receptor for chemokines (DARC) is thought to be involved in scavenging, transendothelial transport, and presentation of neutrophil-specific chemokines. DARC is expressed on endothelial cells and erythrocytes but not on leukocytes. Here, we show that DARC is crucial for chemokine-mediated leukocyte recruitment in vivo. However, we also demonstrate that changes in chemokine and chemokine receptor homeostasis, associated with Darc gene deficiency, exert strong anti-inflammatory effects. Neutrophils from Darc gene-deficient (Darc(-/-)) mice display a more prolonged downregulation of CXCR2 during severe inflammation than neutrophils from wild-type mice. In a CXCR2-dependent model of acid-induced ALI, Darc gene deficiency prevents ALI. Darc(-/-) mice demonstrate fully preserved oxygenation, only a small increase in vascular permeability, and a complete lack of pulmonary neutrophil recruitment. Further analysis reveals that only neutrophils but neither endothelial cells nor erythrocytes from Darc(-/-) mice confer protection from ALI. The protection appears to be due to abolished pulmonary recruitment of neutrophils from Darc(-/-) mice. The generation of neutrophil- platelet aggregates, a key mechanism in both pulmonary neutrophil recruitment and thrombus formation, is also affected by altered CXCR2 homeostasis in Darc(-/-) mice. CXCR2 blockade enhances the formation of platelet-neutrophil aggregates and thereby corrects a formerly unknown bleeding defect in Darc(-/-) mice. In summary, our study suggests that chemokine/chemokine receptor homeostasis plays a previously unrecognized and crucial role in severe ALI.