Impaired host defense, hematopoiesis, granulomatous inflammation and type 1-type 2 cytokine balance in mice lacking CC chemokine receptor 1.
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)-1alpha, 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-1alpha. 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-gamma 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.
Gao
J L
JL
Laboratory of Host Defenses,National Institute of Allergy and Infectio us Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Wynn
T A
TA
Chang
Y
Y
Lee
E J
EJ
Broxmeyer
H E
HE
Cooper
S
S
Tiffany
H L
HL
Westphal
H
H
Kwon-Chung
J
J
Murphy
P M
PM
D000818:Animals; D001228:Aspergillosis / Q000276:immunology*; D001232:Aspergillus fumigatus; D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D002634:Chemotaxis, Leukocyte; D016207:Cytokines / Q000378:metabolism*; D018390:Gene Targeting; D006099:Granuloma / Q000276:immunology*; D006410:Hematopoiesis; D006412:Hematopoietic Stem Cells / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D015847:Interleukin-4 / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016296:Mutagenesis / Q000235:genetics; D009504:Neutrophils / Q000276:immunology*; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D012555:Schistosomiasis mansoni / Q000276:immunology
C515301:Ccr1 protein, mouse; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D016207:Cytokines; D019402:Macrophage Inflammatory Proteins; D054389:Receptors, CCR1; D019707:Receptors, Chemokine; D018121:Receptors, Cytokine; D015847:Interleukin-4; D007371:Interferon-gamma; D002118:Calcium