DEFECTS IN MACROPHAGE RECRUITMENT AND HOST-DEFENSE IN MICE LACKING THE CCR2 CHEMOKINE RECEPTOR

Chemokines are a structurally related family of cytokines that are imp ortant for leukocyte trafficking. The C-C chemokine monocyte chemoattr actant protein-1 (MCP-1) is a potent monocyte activator in vitro and h as 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 homologu es. CCR2 has also recently been demonstrated to be a fusion cofactor f or several HIV isolates. To investigate the normal physiological funct ion of CCR2, we generated mice with a targeted disruption of the ccr2 gene. Mice deficient for CCR2 developed normally and had no hematopoie tic abnormalities. However, ccr2(-/-) mice failed to recruit macrophag es in an experimental peritoneal inflammation model. In addition, thes e mice were unable to clear infection by the intracellular bacteria, L isteria monocytogenes. These results suggest that CCR2 has a nonredund ant role as a major mediator of macrophage recruitment and host defens e against bacterial pathogens and that MCP-1 and other CCR2 ligands ar e effectors of those functions.