Neutrophils are indispensable for hematopoietic stem cell mobilization induced by interleukin-8 in mice

Abstract

The CXC chemokine interleukin-8 (IL-8͞CXCL8) 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 ␤2-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.metalloproteinases ͉ MMP-9 ͉ adhesion molecules ͉ bone marrow ͉ G-CSF

Innate immunity as orchestrator of stem cell mobilization

“…28,61 Mobilization could also be achieved by the administration of some types of polysaccharides (for example, zymosan or fucoidans) that in animal models have been demonstrated to efficiently mobilize HSPCs within 1 h after a single injection. 66,67 Elements of innate immunity involved in stem cell mobilization Evidence from our, [41][42][43][44]68 and other laboratories 69,70 indicates that innate immunity orchestrates egress of HSPCs from BM into PB. Innate or natural immunity is inborn and thus naturally present in an organism; it does not require previous sensitization to an antigen.…”

“…This is based on the observations that (i) granulocytes are the first cells to egress from BM during mobilization, as reported by others and by us, 22 and (ii) the mobilization process is severely impaired in animals that lack granulocytes 69 . Thus, granulocytes have an important role at several steps of mobilization ( Figure 3) and CC cleavage fragments (C5a and desArg C5a) orchestrate this process directly by activating these cells in BM and chemoattracting them into the PB.…”

Mechanisms of G-CSF-mediated hematopoietic stem and progenitor mobilization

“…Depletion of neutrophils 84 or administration of anti-MMP-9 antibodies 85 inhibits the rapid mobilization seen in response to the chemokine IL-8. Moreover, one report suggested that MMP-9-deficient mice have a mobilization defect in response to G-CSF.…”

Improving stem cell mobilization strategies: future directions

“…74,[76][77][78] Several studies have shown that G-CSF and other cytokines can mobilize stem cells in protease-deficient mice, suggesting a more complex model in which both protease-dependent and protease-independent pathways contribute to G-CSFinduced mobilization of stem cells. 77,79,80 Recent data show that G-CSF reduces osteoblast activity and decreases SDF-1a mRNA expression, suggesting a protease-independent mechanism through which G-CSF could regulate stem cell mobilization. 81 Thus, the biological mechanisms through which cytokines induce PBSC mobilization are complex and not completely understood.…”