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The Role of CC Chemokine Receptor 2 in Alveolar Monocyte and Neutrophil Immigration in Intact Mice

Department of Internal Medicine, Justus-Liebig-University, Giessen; Medical Policlinic, University of Munich, Munich; Institute for Animal Physiology, University of Munich, Munich, Germany; Department of Microbiology, University of Texas at Austin, Austin, Texas; and Department of Surgery, North Shore University Hospital, Manhasset, New York

Correspondence and requests for reprints should be addressed to Ulrich A. Maus, Ph.D., Department of Internal Medicine, Justus-Liebig-University, Klinikstrasse 36, Giessen 35392, Germany. E-mail: ulrich.a.maus{at}med.uni-giessen.de

The CC chemokine ligand 2 (CCL2) (JE, monocyte chemotactic protein-1 [MCP-1]) and its CC chemokine receptor 2 (CCR2) are critical regulators of monocyte/macrophage trafficking. Recently, we demonstrated that application of exogenous CCL2 in the lungs of mice induced monocyte accumulation in the airspace, whereas combined bronchoalveolar instillation of CCL2 and Escherichia coli endotoxin provoked both enhanced monocyte accumulation and extensive neutrophil influx associated with loss of pulmonary endothelial/epithelial barrier function. In this study, we investigated the role of the CCL2 receptor CCR2 in alveolar leukocyte traffic. In CCR2 knockout mice or wild-type mice treated with the anti-CCR2–blocking monoclonal antibody MC21, monocyte accumulation in response to alveolar CCL2 or CCL2 plus endotoxin was inhibited by more than 90%. Unexpectedly, alveolar neutrophil accumulation in the CCL2/lipopolysaccharide (LPS) model was also drastically reduced by both approaches of CCR2 function interference. When wild-type mice treated with anti–Gr-1 monoclonal antibody to deplete neutrophils selectively or treated with antileukinate, a CXC receptor inhibitor, were challenged with alveolar CCL2 plus LPS, alveolar monocyte accumulation was markedly decreased. Wild-type mice treated with MC21 to block CCR2 function or with anti–Gr-1 to deplete neutrophils did not exhibit the vascular leakage that typically accompanies inflammation triggered by CCL2 and LPS in wild-type mice. These findings confirm a central role for CCR2 in the process of alveolar monocyte recruitment in response to CCL2 alone and combined CCL2 plus LPS and reveal a previously unobserved interdependence between monocyte and neutrophil trafficking that has important implications for the concomitant increase in vascular permeability.

Key Words: lung • monocyte • CC chemokine receptor 2 • CC chemokine ligand 2 • inflammation

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