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.
Boring
L
L
Gladstone Institute of Cardiovascular Disease, University of California, San Francisco 94141-9100, USA.
Gosling
J
J
Chensue
S W
SW
Kunkel
S L
SL
Farese
R V
RV
Broxmeyer
H E
HE
Charo
I F
IF
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D018932:Chemokine CCL2 / Q000494:pharmacology; D018925:Chemokines / Q000494:pharmacology; D002634:Chemotaxis, Leukocyte / Q000235:genetics / Q000502:physiology*; D016207:Cytokines / Q000096:biosynthesis*; D004622:Embryo, Mammalian; D015769:Granuloma, Respiratory Tract / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000502:physiology; D006801:Humans; D008171:Lung Diseases / Q000276:immunology / Q000503:physiopathology; D008198:Lymph Nodes / Q000276:immunology; D016676:Macrophages, Alveolar / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000502:physiology*; D009163:Mycobacterium bovis; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000096:biosynthesis; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000172:deficiency* / Q000502:physiology*; D011994:Recombinant Proteins / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology; D014158:Transcription, Genetic; D014373:Tuberculin
C515334:CCR2 protein, human; C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D018925:Chemokines; D016207:Cytokines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D011994:Recombinant Proteins; D014373:Tuberculin