Chemokines are a large family of structurally related secreted proteins that are important for leukocyte trafficking (1
). The regulated interaction of chemokines with their respective receptors are thought to mediate the controlled recruitment of specific leukocyte subpopulations required during host defense and inflammation (4
). The specific biological functions of chemokines and their receptors has been difficult to predict, since most chemokines bind more than one receptor and most chemokine receptors bind more than one chemokine ligand in vitro. The analysis of mutant mice lacking a single chemokine ligand or chemokine receptor gene has been useful for determining some of their specific physiological functions. Nonredundant roles in neutrophil and eosinophil recruitment (5
), hematopoiesis (5
), inflammatory response to viral infection (9
), and neutrophil-mediated host defense, granuloma formation, and cytokine balance (6
) have been demonstrated in mice lacking the chemokine receptors CXCR2 and CCR1 and the chemokine ligands macrophage inflammatory protein (MIP) -1α, stromal cell-derived factor-1 (SDF-1), and eotaxin. Although many chemokines including MIP-1α are chemotactic for monocytes in vitro and several chemokine receptors including CCR1 are expressed on monocytes and macrophages, no chemokines or receptors have been identified so far with a specific role in monocyte or macrophage function.
The chemokine ligand monocyte chemoattractant protein-1 (MCP-1) is a potent in vitro monocyte activator that has been associated with monocytic infiltration in several inflammatory diseases (10
). Two related human receptors, CCR2A and CCR2B, have been identified that mediate in vitro responses to MCP-1, and one homologous murine receptor, CCR2, has been identified that mediates in vitro responses to the murine MCP-1 analogue, JE (11
). Both human and murine CCR2 function as receptors for several other close structural homologues of MCP-1 (13
), and human CCR2 can also function as a fusion coreceptor for several HIV isolates (18
). Transgenic mouse models have demonstrated monocyte/macrophage recruitment to sites of human MCP-1 or murine JE expression (20
), and neutralizing antibody studies have implicated MCP-1 as a major mediator of macrophage recruitment in several inflammatory models (23
). These studies have suggested that MCP-1 is important for monocyte/macrophage recruitment in vivo, and that CCR2 may mediate such in vivo responses. To determine if CCR2 may play a role in macrophage recruitment and function, we have generated mice with a targeted disruption of the ccr2
gene. Our studies indicate that CCR2 has a nonredundant function as a major mediator of macrophage recruitment and host defense to bacterial infection.