Dominant Myelopoietic Effector Functions Mediated by Chemokine Receptor CCR1

doi:10.1084/jem.189.12.1987

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J. Exp. Med., Volume 189, Number 12, June 21, 1999 1987-1992

Dominant Myelopoietic Effector Functions Mediated by Chemokine Receptor CCR1

By Hal E. Broxmeyer,^* Scott Cooper,^* Giao Hangoc,^* Ji-Liang Gao,^§ and Philip M. Murphy^§

From the ^* Department of Microbiology/Immunology, the Department of Medicine, and the Walther Oncology Center, Indiana University School of Medicine, Indianapolis, Indiana 46202; the Walther Cancer Institute, Indianapolis, Indiana 46208; and the ^§ Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892

Macrophage inflammatory protein (MIP)-1 $alpha$ , a CC chemokine, enhances proliferation of mature subsets of myeloid progenitor cells(MPCs), suppresses proliferation of immature MPCs, and mobilizesmature and immature MPCs to the blood. MIP-1 $alpha$ binds at least threechemokine receptors. To determine if CCR1 was dominantly mediatingthe above activities of MIP-1 $alpha$ , CCR1-deficient ( $-$ / $-$ ) mice, producedby targeted gene disruption, were used. MIP-1 $alpha$ enhanced colonyformation of marrow granulocyte/macrophage colony-forming units(CFU-GM), responsive to stimulation by granulocyte/macrophagecolony-stimulating factor (GM-CSF), and CFU-M, responsive to stimulationby M-CSF, from littermate control CCR1^+/+ but not CCR1^/ mice. Moreover, MIP-1 $alpha$ did not mobilize MPCs to the blood orsynergize with G-CSF in this effect in CCR1^/ mice. However, CCR1^/ mice were increased in sensitivity to MPC mobilizing effectsof G-CSF. Multi-growth factor-stimulated MPCs in CCR1^/ and CCR1^+/+ marrow were equally sensitive to inhibition by MIP-1 $alpha$ . Theseresults implicate CCR1 as a dominant receptor for MIP-1 $alpha$ enhancementof proliferation of lineage-committed MPCs and for mobilizationof MPCs to the blood. CCR1 is not a dominant receptor for MIP-1 $alpha$ suppression of MPC proliferation, but it does negatively impactG-CSF-induced MPCmobilization.

Key words: CC chemokine receptor 1; macrophage inflammatory protein 1 $alpha$ ; progenitor cells; proliferation; mobilization

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