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 mon onuclear leukocytes and has been implicated in the pathogenesis of ath erosclerosis and granulomatous lung disease, To determine the role of MCP-1 and related family members in vivo, we used homologous recombina tion in embryonic stem cells to generate mice with a targeted disrupti on of C-C chemokine receptor 2 (CCR2), the receptor for MCP-1, CCR2(-/ -) mice were born at the expected Mendelian ratios and developed norma lly, In response to thioglycollate, the recruitment of peritoneal macr ophages decreased selectively, In in vitro chemotaxis assays, CCR2(-/- ) leukocytes failed to migrate in response to MCP-1, Granulomatous lun g 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 i nterferon 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 hyp ersensitivity responses and production of Th1-type cytokines, These da ta suggest an important and unexpected role for CCR2 activation in mod ulating the immune response, as well as in recruiting monocytes/macrop hages to sites of inflammation.