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From the * Laboratory of Host Defenses, 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)-1
Laboratory of Parasitic Diseases, and § Laboratory of Clinical
Investigation, National Institute of Allergy and Infectious Diseases,
Laboratory of Mammalian Genes
and Development, National Institute of Child Health and Human Development, National Institutes
of Health, Bethesda, Maryland 20892; and ¶ Departments of Microbiology/Immunology and
Medicine and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis,
Indiana 46202-5121
, 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-1
. 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-
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.
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