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

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ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

Gao, J. L., Wynn, T. A., Chang, Y., Lee, E. J., Broxmeyer, H. E., Cooper, S., Tiffany, H. L., Westphal, H., Kwon-Chung, J., & Murphy, P. M. (1997). Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1. Journal of Experimental Medicine, 185(11), 1959-1968. https://doi.org/10.1084/jem.185.11.1959