Advertisement

International Journal of Hematology

, Volume 85, Issue 5, pp 390–396 | Cite as

Surface Expression of Neutrophil CXCR4 is Down-Modulated by Bacterial Endotoxin

  • Hyun Kyung Kim
  • Ji-Eun Kim
  • Junho Chung
  • Kyou-Sup Han
  • Han-Ik ChoEmail author
Article

Abstract

The chemokine receptor CXCR4 and its unique ligand, stromal-derived factor 1 (SDF-1), play critical roles in the retention of hematopoietic cells within bone marrow and in their mobilization into the circulation. Surface CXCR4 down-regulation in hematopoietic cells is associated with a loss of retention of the cells in bone marrow. Lipopolysaccharide (LPS), commonly referred to as endotoxin, induces neutrophilia in vivo, but the mechanism of mobilization related to neutrophilia has not been fully clarified. We show that LPS reduces CXCR4 surface expression in a dose- and time-dependent manner in neutrophils and monocytes, but not in lymphocytes. Polymyxin B neutralization of LPS in culture supernatants still induced this down-modulation, and LPS-stimulated neutrophils released interferon γ and interleukin 1β. These results provide evidence that CXCR4 down-regulation can be attributed to soluble factors released by neutrophils upon LPS treatment. Moreover, LPS treatment increased CXCR4 messenger RNA in neutrophils, suggesting that the down-regulation of surface CXCR4 is caused by a posttranslational mechanism, and the chemotactic migration of neutrophils in response to SDF-1 was reduced by LPS pretreatment.Thus, the present study has shown that by down-regulating neutrophil CXCR4 expression and attenuating neutrophil responsiveness to SDF-1, LPS can mobilize neutrophils from bone marrow to the peripheral blood through reducing neutrophil retention in bone marrow.

Key words

Endotoxin Neutrophil CXCR4 

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect. 2002;4:903–914.CrossRefPubMedGoogle Scholar
  2. 2.
    Zarember KA, Godowski PJ. Tissue expression of human Toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products, and cytokines. J Immunol. 2002;168:554–561.CrossRefPubMedGoogle Scholar
  3. 3.
    Wagner JG, Roth RA. Neutrophil migration during endotoxemia. J Leukoc Biol. 1999;66:10–24.CrossRefPubMedGoogle Scholar
  4. 4.
    Wolff SM, Rubenstein M, Mulholland JH, Alling DW. Comparison of hematologic and febrile response to endotoxin in man. Blood. 1965;26:190–201.PubMedGoogle Scholar
  5. 5.
    Granowitz EV, Porat R, Mier JW, et al. Hematologic and immuno-modulatory effects of an interleukin-1 receptor antagonist coinfu- sion during low-dose endotoxemia in healthy humans. Blood. 1993;82:2985–2990.PubMedGoogle Scholar
  6. 6.
    Link DC. Neutrophil homeostasis: a new role for stromal cell-derived factor-1. Immunol Res. 2005;32:169–178.CrossRefPubMedGoogle Scholar
  7. 7.
    Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–1767.CrossRefPubMedGoogle Scholar
  8. 8.
    Ma Q, Jones D, Springer TA. The chemokine receptor CXCR4 is required for the retention of B lineage and granulocytic precursors within the bone marrow microenvironment. Immunity. 1999;10:463–471.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim HK, De La Luz Sierra M, Williams CK, Gulino AV, Tosato G. G-CSF down-regulation of CXCR4 expression identified as a mechanism for mobilization of myeloid cells. Blood. 2006;108:812–820.CrossRefPubMedPubMedCentralGoogle Scholar
  10. 10.
    Martin C, Burdon PC, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity. 2003;19:583–593.CrossRefPubMedGoogle Scholar
  11. 11.
    Aiuti A, Webb IJ, Bleul C, Springer T, Gutierrez-Ramos JC. The chemokine SDF-1 is a chemoattractant for human CD34+ hemato- poietic progenitor cells and provides a new mechanism to explain the mobilization of CD34+ progenitors to peripheral blood. J Exp Med. 1997;185:111–120.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Valenzuela-Fernandez A, Planchenault T, Baleux F, et al. Leukocyte elastase negatively regulates stromal cell-derived factor-1 (SDF-1)/CXCR4 binding and functions by amino-terminal processing of SDF-1 and CXCR4. J Biol Chem. 2002;277:15677–15689.CrossRefPubMedGoogle Scholar
  13. 13.
    Levesque JP, Hendy J, Takamatsu Y, Simmons PJ, Bendall LJ. Disruption of the CXCR4/CXCL12 chemotactic interaction during hematopoietic stem cell mobilization induced by GCSF or cyclophosphamide. J Clin Invest. 2003;111:187–196.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Forster R, Kremmer E, Schubel A, et al. Intracellular and surface expression of the HIV-1 coreceptor CXCR4/fusin on various leukocyte subsets: rapid internalization and recycling upon activation. J Immunol. 1998;160:1522–1531.PubMedGoogle Scholar
  15. 15.
    Brelot A, Heveker N, Montes M, Alizon M. Identification of residues of CXCR4 critical for human immunodeficiency virus coreceptor and chemokine receptor activities. J Biol Chem. 2000;275:23736–23744.CrossRefGoogle Scholar
  16. 16.
    Nagase H, Miyamasu M, Yamaguchi M, et al. Cytokine-mediated regulation of CXCR4 expression in human neutrophils. J Leukoc Biol. 2002;71:711–717.Google Scholar
  17. 17.
    Wang J, Guan E, Roderiquez G, Calvert V, Alvarez R, Norcross MA. Role of tyrosine phosphorylation in ligand-independent sequestration of CXCR4 in human primary monocytes-macrophages. J Biol Chem. 2001;276:49236–49243.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Gallay P, Jongeneel CV, Barras C, et al. Short time exposure to lipopolysaccharide is sufficient to activate human monocytes. J Immunol. 1993;150:5086–5093.PubMedPubMedCentralGoogle Scholar
  19. 19.
    Suratt BT, Petty JM, Young SK, et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood. 2004;104:565–571.CrossRefGoogle Scholar
  20. 20.
    Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell. 2004;116:769–778.CrossRefPubMedGoogle Scholar
  21. 21.
    Ponomaryov T, Peled A, Petit I, et al. Induction of the chemokine stromal-derived factor-1 following DNA damage improves human stem cell function. J Clin Invest. 2000;106:1331–1339.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Broxmeyer HE, Orschell CM, Clapp DW, et al. Rapid mobilization of murine and human hematopoietic stem and progenitor cells with AMD3100, a CXCR4 antagonist. J Exp Med. 2005;201:1307–1318.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Mechanic RC, Frei E 3rd, Landy M, Smith WW. Quantitative studies of human leukocytic and febrile response to single and repeated doses of purified bacterial endotoxin. J Clin Invest. 1962;41:162–172.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Velders GA, van Os R, Hagoort H, et al. Reduced stem cell mobilization in mice receiving antibiotic modulation of the intestinal flora: involvement of endotoxins as cofactors in mobilization. Blood. 2004;103:340–346.CrossRefPubMedGoogle Scholar
  25. 25.
    Verani A, Sironi F, Siccardi AG, Lusso P, Vercelli D. Inhibition of CXCR4-tropic HIV-1 infection by lipopolysaccharide: evidence of different mechanisms in macrophages and T lymphocytes. J Immunol. 2002;168:6388–6395.CrossRefPubMedGoogle Scholar
  26. 26.
    Kucia M, Jankowski K, Reca R, et al. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol. 2004;35:233–245.CrossRefPubMedGoogle Scholar
  27. 27.
    Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol. 2004;25:75–84.CrossRefPubMedGoogle Scholar
  28. 28.
    Bruhl H, Cohen CD, Linder S, Kretzler M, Schlondorff D, Mack M. Post-translational and cell type-specific regulation of CXCR4 expression by cytokines. Eur J Immunol. 2003;33:3028–3037.CrossRefPubMedGoogle Scholar
  29. 29.
    Xu L, Khandaker MH, Barlic J, et al. Identification of a novel mechanism for endotoxin-mediated down-modulation of CC chemokine receptor expression. Eur J Immunol. 2000;30:227–235.CrossRefPubMedGoogle Scholar
  30. 30.
    Fernandis AZ, Cherla RP, Chernock RD, Ganju RK. CXCR4/ CCR5 down-modulation and chemotaxis are regulated by the pro- teasome pathway. J Biol Chem. 2002;277:18111–18117.CrossRefPubMedGoogle Scholar
  31. 31.
    Cassatella MA. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol. 1999;73:369–509.CrossRefPubMedGoogle Scholar
  32. 32.
    Yeaman GR, Collins JE, Currie JK, Guyre PM, Wira CR, Fanger MW. IFN-γ is produced by polymorphonuclear neutrophils in human uterine endometrium and by cultured peripheral blood polymorphonuclear neutrophils. J Immunol. 1998;160:5145–5153.PubMedGoogle Scholar
  33. 33.
    Khandaker MH, Xu L, Rahimpour R, et al. CXCR1 and CXCR2 are rapidly down-modulated by bacterial endotoxin through a unique agonist-independent, tyrosine kinase-dependent mechanism. J Immunol. 1998;161:1930–1938.PubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2007

Authors and Affiliations

  • Hyun Kyung Kim
    • 1
    • 2
  • Ji-Eun Kim
    • 1
    • 2
  • Junho Chung
    • 2
    • 3
  • Kyou-Sup Han
    • 1
  • Han-Ik Cho
    • 1
    Email author
  1. 1.Department of Laboratory MedicineSeoul University College of Medicine and Seoul National University HospitalSeoulRepublic of Korea
  2. 2.Cancer Research InstituteSeoul National University College of MedicineSeoulKorea
  3. 3.Department of Biochemistry and Molecular BiologySeoul National University College of MedicineSeoulKorea

Personalised recommendations