Dominant Myelopoietic Effector Functions Mediated by Chemokine Receptor CCR1

Macrophage inflammatory protein (MIP)-1α, a CC chemokine, enhances proliferation of mature subsets of myeloid progenitor cells (MPCs), suppresses proliferation of immature MPCs, and mobilizes mature and immature MPCs to the blood. MIP-1α binds at least three chemokine receptors. To determine if CCR1 was dominantly mediating the above activities of MIP-1α, CCR1-deficient (−/−) mice, produced by targeted gene disruption, were used. MIP-1α enhanced colony formation of marrow granulocyte/macrophage colony-forming units (CFU-GM), responsive to stimulation by granulocyte/macrophage colony-stimulating factor (GM-CSF), and CFU-M, responsive to stimulation by M-CSF, from littermate control CCR1(+/+) but not CCR1(−/−) mice. Moreover, MIP-1α did not mobilize MPCs to the blood or synergize with G-CSF in this effect in CCR1(−/−) mice. However, CCR1(−/−) mice were increased in sensitivity to MPC mobilizing effects of G-CSF. Multi-growth factor–stimulated MPCs in CCR1(−/−) and CCR1(+/+) marrow were equally sensitive to inhibition by MIP-1α. These results implicate CCR1 as a dominant receptor for MIP-1α enhancement of proliferation of lineage-committed MPCs and for mobilization of MPCs to the blood. CCR1 is not a dominant receptor for MIP-1α suppression of MPC proliferation, but it does negatively impact G-CSF–induced MPC mobilization.