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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.

Pubmed ID: 9366570

Authors

  • Boring L
  • Gosling J
  • Chensue SW
  • Kunkel SL
  • Farese RV
  • Broxmeyer HE
  • Charo IF

Journal

The Journal of clinical investigation

Publication Data

November 15, 1997

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK-53674
  • Agency: NHLBI NIH HHS, Id: HL-52773
  • Agency: NHLBI NIH HHS, Id: HL-56416

Mesh Terms

  • Animals
  • Bone Marrow Cells
  • Chemokine CCL2
  • Chemokines
  • Chemotaxis, Leukocyte
  • Cytokines
  • Embryo, Mammalian
  • Granuloma, Respiratory Tract
  • Hematopoietic Stem Cells
  • Humans
  • Lung Diseases
  • Lymph Nodes
  • Macrophages, Alveolar
  • Mice
  • Mice, Knockout
  • Monocytes
  • Mycobacterium bovis
  • Receptors, CCR2
  • Receptors, CCR5
  • Receptors, Chemokine
  • Recombinant Proteins
  • Th1 Cells
  • Transcription, Genetic
  • Tuberculin