Neutrophils Are Indispensable for Hematopoietic Stem Cell Mobilization Induced by Interleukin-8 in Mice

• Published in: Proceedings of the National Academy of Sciences - PNAS 2002-04, Vol.99 (9), p.6228-6233
• Main Authors: Johannes F. M. Pruijt, Verzaal, Perry, van Os, Ronald, Evert-Jan F. M. de Kruijf, Marianke L. J. van Schie, Mantovani, Alberto, Vecchi, Annunciata, Ivan J. D. Lindley, Willemze, Roel, Starckx, Sofie, Opdenakker, Ghislain, Fibbe, Willem E.
• Format: Article
• Language: English
• Subjects: Animals; Antibodies; Antibodies, Monoclonal - metabolism; Biological Sciences; Blood; Blood plasma; Blood transfusion; Bone marrow; Cells; Cells, Cultured; Cytokines; Dose-Response Relationship, Drug; Flow Cytometry; Hematopoietic stem cell mobilization; Hematopoietic stem cells; Hematopoietic Stem Cells - metabolism; Interleukin-8 - metabolism; Matrix Metalloproteinase 9 - blood; Mice; Mice, Inbred BALB C; Neutropenia - metabolism; Neutrophils; Neutrophils - metabolism; Neutrophils - physiology; Progenitor cells; Recombinant Proteins - metabolism; Rodents; Stem cells; Time Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.092112999

The CXC chemokine interleukin-8 (IL-8/CXCL8) induces rapid mobilization of hematopoietic progenitor cells (HPCs). Previously we showed that mobilization could be prevented completely in mice by pretreatment with neutralizing antibodies against the β2-integrin LFA-1 (CD11a). In addition, murine HPCs do not express LFA-1, indicating that mobilization requires a population of accessory cells. Here we show that polymorphonuclear cells (PMNs) serve as key regulators in IL-8-induced HPC mobilization. The role of PMNs was studied in mice rendered neutropenic by administration of a single injection of antineutrophil antibodies. Absolute neutropenia was observed up to 3-5 days with a rebound neutrophilia at day 7. The IL-8-induced mobilizing capacity was reduced significantly during the neutropenic phase, reappeared with recurrence of the PMNs, and was increased proportionally during the neutrophilic phase. In neutropenic mice, the IL-8-induced mobilizing capacity was restored by the infusion of purified PMNs but not by infusion of mononuclear cells. Circulating metalloproteinase gelatinase B (MMP-9) levels were detectable only in neutropenic animals treated with PMNs in combination with IL-8, showing that in vivo activated PMNs are required for the restoration of mobilization. However, IL-8-induced mobilization was not affected in MMP-9-deficient mice, indicating that MMP-9 is not indispensable for mobilization. These data demonstrate that IL-8-induced mobilization of HPCs requires the in vivo activation of circulating PMNs.