Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1

Ji Liang Gao, Thomas A. Wynn, Yun Chang, Eric J. Lee, Hal Broxmeyer, Scott Cooper, H. Lee Tiffany, Heiner Westphal, June Kwon-Chung, Philip M. Murphy

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Abstract

CC chemokine receptor 1 (CCR1) is expressed in neutrophils, monocytes, lymphocytes, and eosinophils, and binds the leukocyte chemoattractant and hematopoiesis regulator macrophage inflammatory protein (MIP)-1α, as well as several related CC chemokines. Four other CCR subtypes are known; their leukocyte and chemokine specificities overlap with, but are not identical to, CCR1, suggesting that CCR1 has both redundant and specific biologic roles. To test this, we have developed CCR1-deficient mice (-/-) by targeted gene disruption. Although the distribution of mature leukocytes was normal, steady state and induced trafficking and proliferation of myeloid progenitor cells were disordered in -/- mice. Moreover, mature neutrophils from -/- mice failed to chemotax in vitro and failed to mobilize into peripheral blood in vivo in response to MIP-1α. Consistent with this, -/- mice had accelerated mortality when challenged with Aspergillus fumigatus, a fungus controlled principally by neutrophils. To test the role of CCR1 in granuloma formation, we injected Schistosoma mansoni eggs intravenously, and observed a 40% reduction in the size of lung granulomas in -/- mice compared to +/+ littermates. This was associated with increased interferon-γ and decreased interleukin-4 production in -/- versus +/+ lung lymph node cells stimulated with egg-specific antigen, suggesting that CCR1 influences the inflammatory response not only through direct effects on leukocyte chemotaxis, but also through effects on the type 1-type 2 cytokine balance. Thus CCR1 has nonredundant functions in hematopoiesis, host defense, and inflammation.

Original languageEnglish
Pages (from-to)1959-1968
Number of pages10
JournalJournal of Experimental Medicine
Volume185
Issue number11
DOIs
StatePublished - Jun 2 1997

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CCR1 Receptors
Hematopoiesis
Cytokines
Inflammation
Macrophage Inflammatory Proteins
Neutrophils
Leukocytes
Granuloma
Leukocyte Chemotaxis
Myeloid Progenitor Cells
CC Chemokines
Lung
Aspergillus fumigatus
Schistosoma mansoni
Chemotactic Factors
Chemokines
Eosinophils
Interleukin-4
Interferons
Eggs

ASJC Scopus subject areas

  • Immunology

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Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. / Gao, Ji Liang; Wynn, Thomas A.; Chang, Yun; Lee, Eric J.; Broxmeyer, Hal; Cooper, Scott; Tiffany, H. Lee; Westphal, Heiner; Kwon-Chung, June; Murphy, Philip M.

In: Journal of Experimental Medicine, Vol. 185, No. 11, 02.06.1997, p. 1959-1968.

Research output: Contribution to journalArticle

Gao, Ji Liang ; Wynn, Thomas A. ; Chang, Yun ; Lee, Eric J. ; Broxmeyer, Hal ; Cooper, Scott ; Tiffany, H. Lee ; Westphal, Heiner ; Kwon-Chung, June ; Murphy, Philip M. / Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. In: Journal of Experimental Medicine. 1997 ; Vol. 185, No. 11. pp. 1959-1968.
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AU - Lee, Eric J.

AU - Broxmeyer, Hal

AU - Cooper, Scott

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