Skip to main content
SpringerLink
Log in

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

  • Published:
International Journal of Hematology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Dobrovolskaia MA, Vogel SN. Toll receptors, CD14, and macrophage activation and deactivation by LPS. Microbes Infect. 2002;4:903–914.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  3. Wagner JG, Roth RA. Neutrophil migration during endotoxemia. J Leukoc Biol. 1999;66:10–24.

    Article  PubMed  CAS  Google Scholar 

  4. Wolff SM, Rubenstein M, Mulholland JH, Alling DW. Comparison of hematologic and febrile response to endotoxin in man. Blood. 1965;26:190–201.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  6. Link DC. Neutrophil homeostasis: a new role for stromal cell-derived factor-1. Immunol Res. 2005;32:169–178.

    Article  PubMed  CAS  Google Scholar 

  7. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006;107:1761–1767.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  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.

    CAS  PubMed  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    Article  CAS  PubMed  Google Scholar 

  20. Fuchs E, Tumbar T, Guasch G. Socializing with the neighbors: stem cells and their niche. Cell. 2004;116:769–778.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  26. Kucia M, Jankowski K, Reca R, et al. CXCR4-SDF-1 signalling, locomotion, chemotaxis and adhesion. J Mol Histol. 2004;35:233–245.

    Article  PubMed  CAS  Google Scholar 

  27. Moser B, Wolf M, Walz A, Loetscher P. Chemokines: multiple levels of leukocyte migration control. Trends Immunol. 2004;25:75–84.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  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.

    Article  PubMed  CAS  Google Scholar 

  31. Cassatella MA. Neutrophil-derived proteins: selling cytokines by the pound. Adv Immunol. 1999;73:369–509.

    Article  PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

  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.

    PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Laboratory Medicine, Seoul University College of Medicine and Seoul National University Hospital, 28, Yeongeon-dong, Jongno-gu, 110-744, Seoul, Republic of Korea

    Hyun Kyung Kim, Ji-Eun Kim, Kyou-Sup Han & Han-Ik Cho

  2. Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea

    Hyun Kyung Kim, Ji-Eun Kim & Junho Chung

  3. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea

    Junho Chung

Authors
  1. Hyun Kyung Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ji-Eun Kim
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Junho Chung
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kyou-Sup Han
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Han-Ik Cho
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Han-Ik Cho.

About this article

Cite this article

Kim, H.K., Kim, JE., Chung, J. et al. Surface Expression of Neutrophil CXCR4 is Down-Modulated by Bacterial Endotoxin. Int J Hematol 85, 390–396 (2007). https://doi.org/10.1532/IJH97.A30613

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1532/IJH97.A30613

Key words

Search

Navigation