CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions

Eash, Kyle J.; Means, Jacquelyn M.; White, Douglas W.; Link, Daniel C.

doi:10.1182/blood-2008-09-177287

Cited by 260 publications

(271 citation statements)

References 48 publications

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“…4 There is evidence that G-CSF breaks the Cxcr4-Cxcl12 bond by activating neutrophil proteases, 5 thereby releasing neutrophils from the BM into the bloodstream. 3,6 However, several findings cannot be explained by the Cxcr4-Cxcl12 breakage concept alone. First, G-CSF can mobilize neutrophils in protease-deficient mice, arguing against the need for protease activation for this process.…”

Section: Introductionmentioning

confidence: 89%

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Köhler

Filippo²,

Hasenberg

et al. 2011

Blood

182

174

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Emergency mobilization of neutrophil granulocytes (neutrophils) from the bone marrow (BM) is a key event of early cellular immunity. The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) stimulates this process, but it is unknown how individual neutrophils respond in situ. We show by intravital 2-photon microscopy that a systemic dose of human clinical-grade G-CSF rapidly induces the motility and entry of neutrophils into blood vessels within the tibial BM of mice. Simultaneously, the neutrophil-attracting chemokine KC (Cxcl1) spikes in the blood. In mice lacking the KC receptor Cxcr2, G-CSF fails to mobilize neutrophils and antibody blockade of Cxcr2 inhibits the mobilization and induction of neutrophil motility in the BM. KC is expressed by megakaryocytes and endothelial cells in situ and is released in vitro by megakaryocytes isolated directly from BM. This production of KC is strongly increased by thrombopoietin (TPO). Systemic G-CSF rapidly induces the increased production of TPO in BM. Accordingly, a single injection of TPO mobilizes neutrophils with kinetics similar to G-CSF, and mice lacking the TPO receptor show impaired neutrophil mobilization after short-term G-CSF administration. Thus, a network of signaling molecules, chemokines, and cells controls neutrophil release from the BM, and their mobilization involves rapidly induced Cxcr2-mediated motility controlled by TPO as a pacemaker. IntroductionNeutrophils are the most abundant and, arguably, the most important leukocyte in the vertebrate immune system. Under normal conditions, human bone marrow (BM) produces ϳ 10 11 neutrophils per day. 1 In "danger situations" such as peripheral infections, the constant release of neutrophils can be dramatically increased within hours, a process termed danger or stress mobilization. 2 The hematopoietic cytokine granulocyte-colony stimulating factor (G-CSF) is central to the danger mobilization of neutrophils in both humans and mice. 3 However, although recombinant G-CSF has been used in clinical hematology for 20 years, the molecular mechanisms by which it mobilizes neutrophils are still not well understood.Neutrophils are restrained in the BM by the binding of their chemokine receptor Cxcr4 to the chemokine Cxcl12, which is expressed in a membrane-associated fashion by BM stromal cells. 4 There is evidence that G-CSF breaks the Cxcr4-Cxcl12 bond by activating neutrophil proteases, 5 thereby releasing neutrophils from the BM into the bloodstream. 3,6 However, several findings cannot be explained by the Cxcr4-Cxcl12 breakage concept alone. First, G-CSF can mobilize neutrophils in protease-deficient mice, arguing against the need for protease activation for this process. 7,8 Second, because neutrophil-specific deletion of Cxcr4 in mice results in much higher numbers of circulating neutrophils compared with wild-type animals, factors other than Cxcr4 must be involved in steering neutrophils into the BM blood sinuses (unless the process is passive). Finally, the specific Cxcr4-antagonist AMD3100 a...

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Section: Introductionmentioning

confidence: 89%

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

Köhler

Filippo²,

Hasenberg

et al. 2011

Blood

182

174

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“…44 G-CSF regulation of CXCR4 has gained much attention as a critical pathway for HSPC release in response to G-CSF. While the role of CXCR4 in the mobilization of myeloid cells, particularly with a contribution of CXCR2, is well-documented, 7,8,10,[13][14][15][16]45 its role in the mobilization of HSPC is not well documented. Previous studies showed that G-CSF administration in man induces a gradual increase in the expression of CXCR4 on bone marrow progenitors (CD34 + or CD38 + cells) over 5 days of treatment.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 Compelling evidence established that CXCR4 and its unique ligand SDF1/CXCL12 are essential for the retention of granulocytes and other myeloid-lineage cells in the bone marrow, and that disruption of CXCR4 signaling is sufficient for mobilization of neutrophils and other myeloid-lineage cells to the peripheral circulation. [9][10][11][12] Patients with WHIM (warts, hypogammaglobulinemia, infections, myelokathexis) are neutropenic because of reduced neutrophil mobilization attributable, in most cases, to "gain-of-function" mutations of CXCR4. 13,14 Selective deletion of CXCR4 in myeloid cells causes a redistribution of neutrophils from the bone marrow to the blood resulting in neutrophilia.…”

Section: Introductionmentioning

confidence: 99%

MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

Salvucci

Jiang²,

Gasperini³

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundMobilization of hematopoietic stem/progenitor cells from the bone marrow to the peripheral blood by granulocyte colony-stimulating factor is the primary means to acquire stem cell grafts for hematopoietic cell transplantation. Since hematopoietic stem/progenitor cells represent a minority of all blood cells mobilized by granulocyte colony-stimulating factor, the underlying mechanisms need to be understood in order to develop selective drugs. Design and MethodsWe analyzed phenotypic, biochemical and genetic changes in bone marrow cell populations from granulocyte colony-stimulating factor-mobilized and control mice, and linked such changes to effective mobilization of hematopoietic stem/progenitor cells. ResultsWe show that granulocyte colony-stimulating factor indirectly reduces expression of surface vascular cell adhesion molecule 1 on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells by promoting the accumulation of microRNA-126 (miR126)-containing microvescicles in the bone marrow extracellular compartment. We found that hematopoietic stem/progenitor cells, stromal cells and endothelial cells readily incorporate these miR126-loaded microvescicles, and that miR126 represses vascular cell adhesion molecule 1 expression on bone marrow hematopoietic stem/progenitor cells, stromal cells and endothelial cells. In line with this, miR126-null mice displayed a reduced mobilization response to granulocyte colony-stimulating factor. ConclusionsOur results implicate miR126 in the regulation of hematopoietic stem/progenitor cell trafficking between the bone marrow and peripheral sites, clarify the role of vascular cell adhesion molecule 1 in granulocyte colony-stimulating factor-mediated mobilization, and have important implications for improved approaches to selective mobilization of hematopoietic stem/progenitor cells.

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“…axis in regulation of immune cells has been investigated, including a subset of monocytes (i.e., Ly6C high monocytes) (12)(13)(14)(15)(16)(17), whether CXCR4 is involved in regulation of another subset of monocytes (i.e., Ly6C low monocytes) is not known.…”

Section: Significancementioning

confidence: 99%

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

Jung

Heishi

Incio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

103

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Antiangiogenic therapy with antibodies against VEGF (bevacizumab) or VEGFR2 (ramucirumab) has been proven efficacious in colorectal cancer (CRC) patients. However, the improvement in overall survival is modest and only in combination with chemotherapy. Thus, there is an urgent need to identify potential underlying mechanisms of resistance specific to antiangiogenic therapy and develop strategies to overcome them. Here we found that anti-VEGFR2 therapy up-regulates both C-X-C chemokine ligand 12 (CXCL12) and C-X-C chemokine receptor 4 (CXCR4) in orthotopic murine CRC models, including SL4 and CT26. Blockade of CXCR4 signaling significantly enhanced treatment efficacy of anti-VEGFR2 treatment in both CRC models. CXCR4 was predominantly expressed in immunosuppressive innate immune cells, which are recruited to CRCs upon anti-VEGFR2 treatment. Blockade of CXCR4 abrogated the recruitment of these innate immune cells. Importantly, these myeloid cells were mostly Ly6Clow monocytes and not Ly6Chigh monocytes. To selectively deplete individual innate immune cell populations, we targeted key pathways in Ly6Clow monocytes (Cx3cr1−/− mice), Ly6Chigh monocytes (CCR2−/− mice), and neutrophils (anti-Ly6G antibody) in combination with CXCR4 blockade in SL4 CRCs. Depletion of Ly6Clow monocytes or neutrophils improved anti-VEGFR2–induced SL4 tumor growth delay similar to the CXCR4 blockade. In CT26 CRCs, highly resistant to anti-VEGFR2 therapy, CXCR4 blockade enhanced anti-VEGFR2–induced tumor growth delay but specific depletion of Ly6G+ neutrophils did not. The discovery of CXCR4-dependent recruitment of Ly6Clow monocytes in tumors unveiled a heretofore unknown mechanism of resistance to anti-VEGF therapies. Our findings also provide a rapidly translatable strategy to enhance the outcome of anti-VEGF cancer therapies.

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CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions

Cited by 260 publications

References 48 publications

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer

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CXCR4 is a key regulator of neutrophil release from the bone marrow under basal and stress granulopoiesis conditions

Cited by 260 publications

References 48 publications

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

G-CSF–mediated thrombopoietin release triggers neutrophil motility and mobilization from bone marrow via induction of Cxcr2 ligands

MicroRNA126 contributes to granulocyte colony-stimulating factor-induced hematopoietic progenitor cell mobilization by reducing the expression of vascular cell adhesion molecule 1

Targeting CXCR4-dependent immunosuppressive Ly6C low monocytes improves antiangiogenic therapy in colorectal cancer

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Targeting CXCR4-dependent immunosuppressive Ly6C ^low monocytes improves antiangiogenic therapy in colorectal cancer