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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2009;29:1787.)
© 2009 American Heart Association, Inc.

Integrative Physiology/Experimental Medicine

Ccl2 and Ccl3 Mediate Neutrophil Recruitment via Induction of Protein Synthesis and Generation of Lipid Mediators

Christoph Andreas Reichel; Markus Rehberg; Max Lerchenberger; Nina Berberich; Peter Bihari; Alexander Georg Khandoga; Stefan Zahler; Fritz Krombach

From the Walter Brendel Centre of Experimental Medicine (C.A.R., M.R., M.L., P.B., A.G.K., F.K.), Munich, and the Department of Pharmacy, Pharmaceutical Biology (N.B., S.Z.), Munich, Ludwig-Maximilians-Universität München, Germany.

Correspondence to Christoph Andreas Reichel, Walter Brendel Centre of Experimental Medicine, Marchioninistr. 15, D-81366 Munich, Germany. E-mail christoph.reichel{at}med.uni-muenchen.de

Objective— Although the chemokines monocyte chemoattractant protein-1 (Ccl2/JE/MCP-1) and macrophage inflammatory protein-1 (Ccl3/MIP-1) have recently been implicated in neutrophil migration, the underlying mechanisms remain largely unclear.

Methods and Results— Stimulation of the mouse cremaster muscle with Ccl2/JE/MCP-1 or Ccl3/MIP-1 induced a significant increase in numbers of firmly adherent and transmigrated leukocytes (>70% neutrophils) as observed by in vivo microscopy. This increase was significantly attenuated in mice receiving an inhibitor of RNA transcription (actinomycin D) or antagonists of platelet activating factor (PAF; BN 52021) and leukotrienes (MK-886; AA-861). In contrast, leukocyte responses elicited by PAF and leukotriene-B₄ (LTB₄) themselves were not affected by actinomycin D, BN 52021, MK-886, or AA-861. Conversely, PAF and LTB₄, but not Ccl2/JE/MCP-1 and Ccl3/MIP-1, directly activated neutrophils as indicated by shedding of CD62L and marked upregulation of CD11b. Moreover, Ccl2/JE/MCP-1- and Ccl3/MIP-1-elicited leakage of fluorescein isothiocyanate dextran as well as collagen IV remodeling within the venular basement membrane were completely absent in neutrophil-depleted mice.

Conclusions— Ccl2/JE/MCP-1 and Ccl3/MIP-1 mediate firm adherence and (subsequent) transmigration of neutrophils via protein synthesis and secondary generation of leukotrienes and PAF, which in turn directly activate neutrophils. Thereby, neutrophils facilitate basement membrane remodeling and promote microvascular leakage.

The present study demonstrates that CC chemokines Ccl2/JE/MCP-1 and Ccl3/MIP-1 mediate firm adherence and (subsequent) transmigration of neutrophils via induction of protein synthesis and secondary generation of leukotrienes and PAF, which in turn directly activate neutrophils. Thereby, neutrophils facilitate basement membrane remodeling and promote microvascular leakage.

Key Words: leukocyte • migration • chemokines • permeability • basement membrane