J. Exp. Med., Volume 186, Number 10, November 17, 1997 1757-1762

BRIEF DEFINITIVE REPORT:
Defects in Macrophage Recruitment and Host Defense in Mice Lacking the CCR2 Chemokine Receptor

By Takao Kurihara,^* Glenn Warr,^§ James Loy, and Rodrigo Bravo^*

From the Department of ^* Oncology and  Experimental Pathology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000; and the ^§ Department of Microbiology, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, Connecticut 06492-7660

Chemokines are a structurally related family of cytokines that are important for leukocyte trafficking. The C-C chemokine monocyte chemoattractant protein-1 (MCP-1) is a potent monocyte activator in vitro and has been associated with monocytic infiltration in several inflammatory diseases. One C-C chemokine receptor, CCR2, has been identified that mediates in vitro responses to MCP-1 and its close structural homologues. CCR2 has also recently been demonstrated to be a fusion cofactor for several HIV isolates. To investigate the normal physiological function of CCR2, we generated mice with a targeted disruption of the ccr2 gene. Mice deficient for CCR2 developed normally and had no hematopoietic abnormalities. However, ccr2^/ mice failed to recruit macrophages in an experimental peritoneal inflammation model. In addition, these mice were unable to clear infection by the intracellular bacteria, Listeria monocytogenes. These results suggest that CCR2 has a nonredundant role as a major mediator of macrophage recruitment and host defense against bacterial pathogens and that MCP-1 and other CCR2 ligands are effectors of those functions.

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• Chen, B. P., Kuziel, W. A., Lane, T. E. (2001). Lack of CCR2 Results in Increased Mortality and Impaired Leukocyte Activation and Trafficking Following Infection of the Central Nervous System with a Neurotropic Coronavirus. J. Immunol. 167: 4585-4592 [Abstract] [Full Text]  
• Chensue, S. W. (2001). Molecular Machinations: Chemokine Signals in Host-Pathogen Interactions. Clin. Microbiol. Rev. 14: 821-835 [Abstract] [Full Text]  
• Carnevale, K. A., Cathcart, M. K. (2001). Calcium-Independent Phospholipase A2 Is Required for Human Monocyte Chemotaxis to Monocyte Chemoattractant Protein 1. J. Immunol. 167: 3414-3421 [Abstract] [Full Text]  
• Mukai, T., Iwasaki, M., Gao, P., Tomura, M., Yashiro-Ohtani, Y., Ono, S., Murai, M., Matsushima, K., Kurimoto, M., Kogo, M., Matsuya, T., Fujiwara, H., Hamaoka, T. (2001). IL-12 plays a pivotal role in LFA-1-mediated T cell adhesiveness by up-regulation of CCR5 expression. J. Leukoc. Biol. 70: 422-430 [Abstract] [Full Text]  
• Low, Q. E. H., Drugea, I. A., Duffner, L. A., Quinn, D. G., Cook, D. N., Rollins, B. J., Kovacs, E. J., DiPietro, L. A. (2001). Wound Healing in MIP-1{alpha}-/- and MCP-1-/- Mice. Am. J. Pathol. 159: 457-463 [Abstract] [Full Text]  
• Peters, W., Scott, H. M., Chambers, H. F., Flynn, J. L., Charo, I. F., Ernst, J. D. (2001). Chemokine receptor 2 serves an early and essential role in resistance to Mycobacterium tuberculosis. Proc. Natl. Acad. Sci. USA 98: 7958-7963 [Abstract] [Full Text]  
• Nesbit, M., Schaider, H., Miller, T. H., Herlyn, M. (2001). Low-Level Monocyte Chemoattractant Protein-1 Stimulation of Monocytes Leads to Tumor Formation in Nontumorigenic Melanoma Cells. J. Immunol. 166: 6483-6490 [Abstract] [Full Text]  
• Cook, D. N., Chen, S.-C., Sullivan, L. M., Manfra, D. J., Wiekowski, M. T., Prosser, D. M., Vassileva, G., Lira, S. A. (2001). Generation and Analysis of Mice Lacking the Chemokine Fractalkine. Mol. Cell. Biol. 21: 3159-3165 [Abstract] [Full Text]  
• Kim, Y., Sung, S.-s. J., Kuziel, W. A., Feldman, S., Fu, S. M., Rose, C. E. Jr (2001). Enhanced Airway Th2 Response After Allergen Challenge in Mice Deficient in CC Chemokine Receptor-2 (CCR2). J. Immunol. 166: 5183-5192 [Abstract] [Full Text]  
• Mack, M., Cihak, J., Simonis, C., Luckow, B., Proudfoot, A. E. I., Bruhl, H., Frink, M., Anders, H.-J., Vielhauer, V., Pfirstinger, J., Stangassinger, M., Schlondorff, D. (2001). Expression and Characterization of the Chemokine Receptors CCR2 and CCR5 in Mice. J. Immunol. 166: 4697-4704 [Abstract] [Full Text]  
• Guleria, I., Pollard, J. W. (2001). Aberrant Macrophage and Neutrophil Population Dynamics and Impaired Th1 Response to Listeria monocytogenes in Colony-Stimulating Factor 1-Deficient Mice. Infect. Immun. 69: 1795-1807 [Abstract] [Full Text]  
• Goebeler, M., Gillitzer, R., Kilian, K., Utzel, K., Brocker, E.-B., Rapp, U. R., Ludwig, S. (2001). Multiple signaling pathways regulate NF-{kappa}B-dependent transcription of the monocyte chemoattractant protein-1 gene in primary endothelial cells. Blood 97: 46-55 [Abstract] [Full Text]  
• Peters, W., Dupuis, M., Charo, I. F. (2000). A Mechanism for the Impaired IFN-{gamma} Production in C-C Chemokine Receptor 2 (CCR2) Knockout Mice: Role of CCR2 in Linking the Innate and Adaptive Immune Responses. J. Immunol. 165: 7072-7077 [Abstract] [Full Text]  
• MacLean, J. A., De Sanctis, G. T., Ackerman, K. G., Drazen, J. M., Sauty, A., DeHaan, E., Green, F. H. Y., Charo, I. F., Luster, A. D. (2000). CC Chemokine Receptor-2 Is Not Essential for the Development of Antigen-Induced Pulmonary Eosinophilia and Airway Hyperresponsiveness. J. Immunol. 165: 6568-6575 [Abstract] [Full Text]  
• Izikson, L., Klein, R. S., Charo, I. F., Weiner, H. L., Luster, A. D. (2000). Resistance to Experimental Autoimmune Encephalomyelitis in Mice Lacking the CC Chemokine Receptor (CCR)2. JEM 192: 1075-1080 [Abstract] [Full Text]  
• , B., , G., , W., , W. (2000). CC Chemokine Receptor 2 Is Critical for Induction of Experimental Autoimmune. JEM 192: 899-906 [Abstract] [Full Text]  
• Unutmaz, D., Xiang, W., Sunshine, M. J., Campbell, J., Butcher, E., Littman, D. R. (2000). The Primate Lentiviral Receptor Bonzo/STRL33 Is Coordinately Regulated with CCR5 and Its Expression Pattern Is Conserved Between Human and Mouse. J. Immunol. 165: 3284-3292 [Abstract] [Full Text]  
• Vicenzi, E., Alfano, M., Ghezzi, S., Gatti, A., Veglia, F., Lazzarin, A., Sozzani, S., Mantovani, A., Poli, G. (2000). Divergent regulation of HIV-1 replication in PBMC of infected individuals by CC chemokines: suppression by RANTES, MIP-1{alpha}, and MCP-3, and enhancement by MCP-1. J. Leukoc. Biol. 68: 405-412 [Abstract] [Full Text]  
• Blease, K., Mehrad, B., Standiford, T. J., Lukacs, N. W., Gosling, J., Boring, L., Charo, I. F., Kunkel, S. L., Hogaboam, C. M. (2000). Enhanced Pulmonary Allergic Responses to Aspergillus in CCR2-/- Mice. J. Immunol. 165: 2603-2611 [Abstract] [Full Text]  
• Sato, N., Ahuja, S. K., Quinones, M., Kostecki, V., Reddick, R. L., Melby, P. C., Kuziel, W. A., Ahuja, S. S. (2000). CC Chemokine Receptor (CCR)2 Is Required for Langerhans Cell Migration and Localization of T Helper Cell Type 1 (Th1)-inducing Dendritic Cells: Absence of CCR2 Shifts the Leishmania major-resistant Phenotype to a Susceptible State Dominated by Th2 Cytokines, B Cell Outgrowth, and Sustained Neutrophilic Inflammation. JEM 192: 205-218 [Abstract] [Full Text]  
• Salcedo, R., Ponce, M. L., Young, H. A., Wasserman, K., Ward, J. M., Kleinman, H. K., Oppenheim, J. J., Murphy, W. J. (2000). Human endothelial cells express CCR2 and respond to MCP-1: direct role of MCP-1 in angiogenesis and tumor progression. Blood 96: 34-40 [Abstract] [Full Text]  
• Andres, P. G., Beck, P. L., Mizoguchi, E., Mizoguchi, A., Bhan, A. K., Dawson, T., Kuziel, W. A., Maeda, N., MacDermott, R. P., Podolsky, D. K., Reinecker, H.-C. (2000). Mice with a Selective Deletion of the CC Chemokine Receptors 5 or 2 Are Protected from Dextran Sodium Sulfate-Mediated Colitis: Lack of CC Chemokine Receptor 5 Expression Results in a NK1.1+ Lymphocyte-Associated Th2-Type Immune Response in the Intestine. J. Immunol. 164: 6303-6312 [Abstract] [Full Text]  

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