The Journal of Experimental Medicine
VeriKine-HS Human IFN-Beta
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© The Rockefeller University Press, 0022-1007/1997/6/1959/ $5.00
The Journal of Experimental Medicine, Volume 185, Number 11, June 2, 1997 1959-1968

Articles

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{ddagger}, Yun Chang§, Eric J. Lee||, Hal E. Broxmeyer, Scott Cooper, H. Lee Tiffany*, Heiner Westphal||, June Kwon-Chung§, and Philip M. Murphy*

From the * Laboratory of Host Defenses, {ddagger} 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

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{alpha}, 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{alpha}. 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.

Address correspondence to Dr. Ji-Liang Gao, Laboratory of Host Defenses, NIAID, Bldg. 10, Rm 11N113, National Institutes of Health, Bethesda, MD 20892.

1Abbreviations used in this paper: BFU-E, erythroid burst-forming unit; CFU-GEMM, granulocyte, erythrocyte, macrophage, megakaryocyte CFU; CFU-GM, granulocyte/macrophage CFU; lps, lipopolysaccharide; MIP, macrophage inflammatory protein; neoR, neomycin resistance gene; ORF, open reading frame; RANTES, reduced on activation normal T expressed and secreted; SEA, schistosome egg antigen; TP, thioglycollateelicited peritoneal.


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