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

Landin Boring, Jennifa Gosling, Stephen W. Chensue, Steven L. Kunkel, Robert V. Farese, Hal Broxmeyer, Israel F. Charo

Research output: Contribution to journalArticle

775 Citations (Scopus)

Abstract

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 γ in the draining lymph nodes. Production of interferon γ 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.

Original languageEnglish
Pages (from-to)2552-2561
Number of pages10
JournalJournal of Clinical Investigation
Volume100
Issue number10
StatePublished - Nov 15 1997

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CC Chemokines
Chemokine Receptors
Knockout Mice
Monocytes
Cytokines
Chemokine CCL2
Interferons
Lung Diseases
CCR2 Receptors
Thioglycolates
Mononuclear Leukocytes
Homologous Recombination
Delayed Hypersensitivity
Peritoneal Macrophages
Chemotaxis
Embryonic Stem Cells
Mycobacterium bovis
Concanavalin A
Granuloma
Atherosclerosis

Keywords

  • Chemokine receptor
  • Chemokines
  • Homologous recombination
  • Inflammation
  • MCP-1

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Boring, L., Gosling, J., Chensue, S. W., Kunkel, S. L., Farese, R. V., Broxmeyer, H., & Charo, I. F. (1997). Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. Journal of Clinical Investigation, 100(10), 2552-2561.

Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. / Boring, Landin; Gosling, Jennifa; Chensue, Stephen W.; Kunkel, Steven L.; Farese, Robert V.; Broxmeyer, Hal; Charo, Israel F.

In: Journal of Clinical Investigation, Vol. 100, No. 10, 15.11.1997, p. 2552-2561.

Research output: Contribution to journalArticle

Boring, L, Gosling, J, Chensue, SW, Kunkel, SL, Farese, RV, Broxmeyer, H & Charo, IF 1997, 'Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice', Journal of Clinical Investigation, vol. 100, no. 10, pp. 2552-2561.
Boring, Landin ; Gosling, Jennifa ; Chensue, Stephen W. ; Kunkel, Steven L. ; Farese, Robert V. ; Broxmeyer, Hal ; Charo, Israel F. / Impaired monocyte migration and reduced type 1 (Th1) cytokine responses in C-C chemokine receptor 2 knockout mice. In: Journal of Clinical Investigation. 1997 ; Vol. 100, No. 10. pp. 2552-2561.
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