Neutrophil-Derived Cathelicidin Promotes Adhesion of Classical Monocytes

• Published in: Circulation research Vol. 112; no. 5; pp. 792 - 801
• Main Authors: Wantha, Sarawuth, Alard, Jean-Eric, Megens, Remco T.A, van der Does, Anne M, Döring, Yvonne, Drechsler, Maik, Pham, Christine T.N, Wang, Ming-Wei, Wang, Ji-Min, Gallo, Richard L, von Hundelshausen, Philipp, Lindbom, Lennart, Hackeng, Tilman, Weber, Christian, Soehnlein, Oliver
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.03.2013
• Subjects: Amino Acid Sequence; Animals; Antimicrobial Cationic Peptides - genetics; Antimicrobial Cationic Peptides - metabolism; Cathelicidins - genetics; Cathelicidins - metabolism; Cell Adhesion - physiology; Cell Communication - physiology; Endothelium, Vascular - metabolism; Humans; Inflammation - metabolism; Inflammation - pathology; Integrins - metabolism; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Molecular Sequence Data; Monocytes - metabolism; Monocytes - pathology; Neutrophils - metabolism; Neutrophils - pathology; Receptors, Formyl Peptide - metabolism; Receptors, Lipoxin - metabolism
• ISSN: 0009-7330; 1524-4571; 1524-4571
• DOI: 10.1161/CIRCRESAHA.112.300666

RATIONALE:The leukocyte response in acute inflammation is characterized by an initial recruitment of neutrophils preceding a second wave of monocytes. Neutrophil-derived granule proteins were suggested to hold an important role in this cellular switch. The exact mechanisms by which neutrophils mediate these processes are only partially understood. OBJECTIVE:To investigate the role of neutrophils and their granule contents in the adhesion of monocyte subpopulations in acute inflammation. METHODS AND RESULTS:Here, we show that neutrophil-derived cathelicidins (humanLL37, mouseCRAMP) induce adhesion of classical monocytes but not of nonclassical monocytes in the mouse cremaster muscle and in in vitro flow chamber assays. CRAMP is released from emigrated neutrophils and then transported across the endothelium, where it is presented to rolling leukocytes. Endothelial-bound cathelicidin activates formyl-peptide receptor 2 on classical monocytes, resulting in monocytic β1- and β2-integrin conformational change toward an extended, active conformation that allows for adhesion to their respective ligands, vascular cell adhesion molecule 1 and intercellular adhesion molecule 1. CONCLUSIONS:These data elucidate a novel mechanism of neutrophil-mediated monocyte recruitment, which could be targeted in conditions where recruitment of classical monocytes plays an unfavorable role.