Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice

Monocyte chemoattractant protein-1 (MCP-1) is a potent agonist for mononuclear leukocytes and has been implicated in the pathogenesis of atherosclerosis and granulomatous lung disease, To determine the role of MCP-1 and related family members in vivo, we used homologous recombination in embryonic stem cells to generate mice with a targeted disruption of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1, CCR2(-/-) mice were born at the expected Mendelian ratios and developed normally, In response to thioglycollate, the recruitment of peritoneal macrophages decreased selectively, In in vitro chemotaxis assays, CCR2(-/-) leukocytes failed to migrate in response to MCP-1, Granulomatous lung disease was induced in presensitized mice by embolization with beads coupled to purified protein derivative (PPD) of Mycobacterium bovis, As compared with wild-type littermates, CCR2(-/-) mice had a decrease in granuloma size accompanied by a dramatic decrease in the level of interferon gamma in the draining lymph nodes, Production of interferon gamma was also decreased in PPD-sensitized splenocytes from CCR2(-/-) mice and in naive splenocytes activated by concanavalin A, We conclude that CCR2(-/-) mice have significant defects in both delayed-type hypersensitivity responses and production of Th1-type cytokines, These data suggest an important and unexpected role for CCR2 activation in modulating the immune response, as well as in recruiting monocytes/macrophages to sites of inflammation.