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 E. Broxmeyer, Israel F. Charo

Research output: Contribution to journalArticle

790 Scopus citations

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

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

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