Chemokine receptor CXCR4–dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells

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Abstract

Regulation of the availability of chemokine SDF-1 (CXCL12) in bone marrow is still not fully understood. Here we describe a unique function for the chemokine receptor CXCR4 expressed on bone marrow endothelial cells, which efficiently internalize circulating SDF-1, resulting in its translocation into the bone marrow. Translocated SDF-1 increased the homing of transplanted human CD34+ hematopoietic progenitors to the bone marrow. The chemokine transporter function of CXCR4 was a characteristic of endothelial and stromal cells but not of hematopoietic cells. Thus, chemokine translocation across the blood–bone marrow barrier allows effective transfer of functional SDF-1 from the periphery to the stem cell niche in the bone marrow during both homeostasis and 'alarm' situations.

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Figure 1: SDF-1 and CXCR4 expression and presentation by bone marrow sinusoids.
Figure 2: CXCR4-dependent translocation of circulating bSDF-1 into the bone marrow.
Figure 3: SDF-1 internalization by human and mouse bone marrow endothelium is CXCR4 dependent.
Figure 4: Transcytosis of SDF-1 by endothelial cells via clathrin-coated pits.
Figure 5: Resecretion of functional bSDF-1 by BMECs.
Figure 6: SDF-1 internalization is exclusive to stromal cells, not to hematopoietic cells.

References

  1. 1

    Nagasawa, T. et al. Defects of B-cell lymphopoiesis and bone-marrow myelopoiesis in mice lacking the CXC chemokine PBSF/SDF-1. Nature 382, 635–638 (1996).

  2. 2

    Tachibana, K. et al. The chemokine receptor CXCR4 is essential for vascularization of the gastrointestinal tract. Nature 393, 591–594 (1998).

  3. 3

    Zou, Y.R., Kottmann, A.H., Kuroda, M., Taniuchi, I. & Littman, D.R. Function of the chemokine receptor CXCR4 in haematopoiesis and in cerebellar development. Nature 393, 595–599 (1998).

  4. 4

    Peled, A. et al. Dependence of human stem cell engrafment and repopulation of NOD/SCID mice on CXCR4. Science 283, 845–848 (1999).

  5. 5

    Muller, A. et al. Involvement of chemokine receptors in breast cancer metastasis. Nature 410, 50–56 (2001).

  6. 6

    Sun, Y.X. et al. Expression of CXCR4 and CXCL12 (SDF-1) in human prostate cancers (PCa) in vivo. J. Cell. Biochem. 89, 462–473 (2003).

  7. 7

    Imai, K. et al. Selective secretion of chemoattractants for haemopoietic progenitor cells by bone marrow endothelial cells: a possible role in homing of haemopoietic progenitor cells to bone marrow. Br. J. Haematol. 106, 905–911 (1999).

  8. 8

    Peled, A. et al. The chemokine SDF-1 stimulates integrin-mediated arrest of CD34+ cells on vascular endothelium under shear flow. J. Clin. Invest. 104, 1199–1211 (1999).

  9. 9

    Ponomaryov, T. et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J. Clin. Invest. 106, 1331–1339 (2000).

  10. 10

    Kortesidis, A. Stromal-derived factor-1 promotes the growth, survival, and development of human bone marrow stromal stem cells. Blood 105, 3793–3801 (2005).

  11. 11

    Peled, A. et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34+ cells: role in transendothelial/stromal migration and engrafment of NOD/SCID mice. Blood 95, 3289–3296 (2000).

  12. 12

    Mazo, I.B. et al. Bone marrow is a major reservoir and site of recruitment for central memory CD8+ T cells. Immunity 22, 259–270 (2005).

  13. 13

    Ceradini, D.J. et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med. 10, 858–864 (2004).

  14. 14

    Kollet, O. et al. HGF, SDF-1, and MMP-9 are involved in stress-induced human CD34+ stem cell recruitment to the liver. J. Clin. Invest. 112, 160–169 (2003).

  15. 15

    De La Luz Sierra, M. et al. Differential processing of stromal-derived factor-1α and stromal-derived factor-1β explains functional diversity. Blood 103, 2452–2459 (2004).

  16. 16

    Petit, I. et al. G-CSF induces stem cell mobilization by decreasing bone marrow SDF-1 and up-regulating CXCR4. Nat. Immunol. 3, 687–694 (2002).

  17. 17

    Levesque, J.P., Hendy, J., Takamatsu, Y., Simmons, P.J. & Bendall, L.J. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J. Clin. Invest. 111, 187–196 (2003).

  18. 18

    Hattori, K. et al. Plasma elevation of stromal-cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood 97, 3354–3360 (2001).

  19. 19

    Shen, H. et al. CXCR-4 desensitization is associated with tissue localization of hematopoietic progenitor cells. J. Immunol. 166, 5027–5033 (2001).

  20. 20

    Middleton, J. et al. Transcytosis and surface presentation of IL-8 by venular endothelial cells. Cell 91, 385–395 (1997).

  21. 21

    Horuk, R. et al. The duffy antigen receptor for chemokines: structural analysis and expression in the brain. J. Leukoc. Biol. 59, 29–38 (1996).

  22. 22

    Rot, A. & von Andrian, U.H. Chemokines in innate and adaptive host defense: basic chemokinese grammar for immune cells. Annu. Rev. Immunol. 22, 891–928 (2004).

  23. 23

    Jamieson, T. et al. The chemokine receptor D6 limits the inflammatory response in vivo. Nat. Immunol. 6, 403–411 (2005).

  24. 24

    Fra, A.M. et al. Scavenging of inflammatory CC chemokines by the promiscuous putatively silent chemokine receptor D6. J. Immunol. 170, 2279–2282 (2003).

  25. 25

    Chaudhuri, A. et al. Detection of Duffy antigen in the plasma membranes and caveolae of vascular endothelial and epithelial cells of nonerythroid organs. Blood 89, 701–712 (1997).

  26. 26

    Amara, A. et al. Stromal cell-derived factor-1α associates with heparan sulfates through the first β-strand of the chemokine. J. Biol. Chem. 274, 23916–23925 (1999).

  27. 27

    Suzuki, G. et al. Loss of SDF-1 receptor expression during positive selection in the thymus. Int. Immunol. 10, 1049–1056 (1998).

  28. 28

    Signoret, N. et al. Phorbol esters and SDF-1 induce rapid endocytosis and down modulation of the chemokine receptor CXCR4. J. Cell Biol. 139, 651–664 (1997).

  29. 29

    Minshall, R.D., Sessa, W.C., Stan, R.V., Anderson, R.G.W. & Malik, A.B. Caveolin regulation of endothelial function. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L1179–L1183 (2003).

  30. 30

    Rafii, S. Isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion. Blood 84, 10–19 (1994).

  31. 31

    Chaussalet, M. et al. Homocysteine modulates the proteolytic potential of human vascular endothelial cells. Biochem. Biophys. Res. Commun. 316, 170–176 (2004).

  32. 32

    Netelenbos, T. et al. Proteoglycans on bone marrow endothelial cells bind and present SDF-1 towards hematopoietic progenitor cells. Leukemia 17, 175–184 (2003).

  33. 33

    Kollet, O. et al. Rapid and efficient homing of human CD34+CD38−/low CXCR4+ stem and progenitor cells to the bone marrow and spleen of NOD/SCID and NOD/SCID/B2mnull mice. Blood 97, 3283–3291 (2001).

  34. 34

    Amara, A. et al. HIV coreceptor downregulation as antiviral principle: SDF-1 α-dependent internalization of the chemokine receptor CXCR4 contributes to inhibition of HIV replication. J. Exp. Med. 186, 139–146 (1997).

  35. 35

    Stumm, R.K. et al. A dual role for the SDF-1/CXCR4 chemokine receptor system in adult brain: isoform-selective regulation of SDF-1 expression modulates CXCR4-dependent neuronal plasticity and cerebral leukocyte recruitment after focal ischemia. J. Neurosci. 22, 5865–5878 (2002).

  36. 36

    Askari, A.T. et al. Effect of stromal-cell-derived-factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 362, 697–703 (2003).

  37. 37

    Dzenko, K.A., Andjelkovic, A.V., Kuziel, W.A. & Pachter, J.S. The chemokine receptor CCR2 mediates the binding and internalization of monocyte chemoattractant protein-1 along brain microvessels. J. Neurosci. 21, 9214–9223 (2001).

  38. 38

    Pablos, J.L. et al. Synoviocyte-derived CXCL12 is displayed on endothelium and induces angiogenesis in rheumatoid arthritis. J. Immunol. 170, 2147–2152 (2003).

  39. 39

    Hitchon, C. et al. Hypoxia-induced production of stromal cell-derived factor 1(CXCL12) and vascular endothelial growth factor by synovial fibroblasts. Arthritis Rheum. 46, 2587–2597 (2002).

  40. 40

    Salvucci, O. et al. Regulation of endothelial cell branching morphogenesis by endogenous chemokine stromal-derived factor-1. Blood 99, 2703–2711 (2002).

  41. 41

    Lambertsen, R.H. & Weiss, L. A model of intramedullary hematopoietic microenvironments based on stereologic study of the distribution of endocloned marrow colonies. Blood 63, 287–297 (1984).

  42. 42

    Lord, B.I. The architecture of bone marrow cell populations. Int. J. Cell Cloning 8, 317–331 (1990).

  43. 43

    Calvi, L.M. et al. Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425, 841–846 (2003).

  44. 44

    Kollet, O. et al. Osteoclasts are involved in stem cell mobilization: cleavage of SDF-1 by cathepsin K. Blood 104, 364A–364A.

  45. 45

    Sipkins, D.A. et al. In vivo imaging of specialized bone marrow endothelial microdomains for tumour engraftment. Nature 435, 969–973 (2005).

  46. 46

    Kiel, M.J. et al. SLAM family receptors distinguish hematopoietic stem and progenitor cells and reveal endothelial niches for stem cells. Cell 121, 1109–1121 (2005).

  47. 47

    Mack, M. et al. Aminooxypentane-RANTES induces CCR5 internalization but inhibits recycling: a novel inhibitory mechanism of HIV infectivity. J. Exp. Med. 187, 1215–1224 (1998).

  48. 48

    Oynebraten, I., Bakke, O., Brandtzaeg, P., Johansen, F.E. & Haraldsen, G. Rapid chemokine secretion from endothelial cells originates from two distinct compartments. Blood 104, 314–320 (2004).

  49. 49

    Wolff, B., Burns, A.R., Middleton, J. & Rot, A. Endothelial cells “memory” of inflammatory stimulation: human venular endothelial cells store interleukin 8 in weibel-palade bodies. J. Exp. Med. 188, 1757–1762 (1998).

  50. 50

    Rafii, S. et al. isolation and characterization of human bone marrow microvascular endothelial cells: hematopoietic progenitor cell adhesion. Blood 84, 10–19 (1994).

  51. 51

    Spiegel, A. et al. Unique SDF-1 induced activation of human precursor-B ALL cells as a result of altered CXCR4 expression and signaling. Blood 103, 2900–2907 (2004).

  52. 52

    Song, L. & Pachter, S. Monocyte chemoattractant protein-1 alters expression of tight junction-associated proteins in brain microvascular endothelial cells. Microvasc. Res. 67, 78–89 (2004).

  53. 53

    Pelletier, A.J. et al. Presentation of chemokine SDF-1α by fibronectin mediates directed migration of T cells. Blood 96, 2682–2690 (2000).

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Acknowledgements

We thank B. Frisch and B. Lifschitz–Mercer (Sourasky Medical Center, Tel-Aviv, Israel) for providing human bone marrow specimens; and A. Globerson, D. Zipori, R. Alon and S. Berrih-Aknin for critical remarks and discussions. Supported by The Israel Science Foundation (794/04) and Ares-Serono Group and by the Edith Stein Professional Chair of Immunology (T.L.).

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Correspondence to Tsvee Lapidot.

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