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A co-stimulatory signal through ICAM-β2 integrin-binding potentiates neutrophil phagocytosis

Nature Medicine volume 5, pages 231–235 (1999)Cite this article

Abstract

The β2 integrin LFA–1 (lymphocyte function associated antigen; CD11a/CD18) is the common ligand for the intercellular adhesion molecules1,2,3,4 (ICAMs). Integrins support cell function by providing co-stimulatory second signals that are a precondition for full cell activation first described for ICAM–1–binding to LFA–1 in lymphocytes3,4. Integrins can also serve to activate functions associated with distinct subunits of other integrins5. In addition to LFA–1, neutrophils express the β2 integrin Mac–1 (CD11b/CD18; CR3) that apparently contains multiple sites that bind invading microbes directly or through surface–fixed C3 (ref. 6), resulting in activation of the phagocyte function7,8,9,10,11. Expression of the LFA–1 counter–receptor ICAM–1 on endothelial cells occurs only at the site of inflammation12,13. Therefore, in neutrophils, ICAM–1 ligand binding could, as with lymphocytes, also play a part as a co–stimulatory signal to induce full phagocytotic function. We show that in neutrophils, the LFA–1 ligand interaction is the stimulatory signal to express full phagocytotic activation. This is best demonstrated by the rapid association of Streptococcus pyogenes with neutrophils, followed by ingestion, strong oxidative–burst induction and enhanced killing of these bacteria, which are well–known for their resistance to human neutrophil defense. These findings may contribute to the development of therapeutic strategies targeting the modulation of ICAM–1–leukocyte interaction.

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Figure 1: Microbial and LFA–1–mediated Mac–1 expression on human neutrophils and the resulting effects on the binding of microorganisms.
Figure 2: LFA–1–mediated binding and ingestion of S. pyogenes, S. aureus, and C. albicans.
Figure 3: Oxidative burst and killing.
Figure 4: β2 integrins as two–way signaling molecules.

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References

  1. Hynes, R.O. Integrins: Versatility, modulation, and signalling in cell adhesion. Cell 69, 11–25 ( 1992).

    Article  CAS  Google Scholar 

  2. Springer, T.A. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301– 314 (1994).

    Article  CAS  Google Scholar 

  3. Marlin, S.D. & Springer, T.A. Purified intercellular adhesion molecule–1 (ICAM–1) is a ligand for lymphocyte function–associated antigen 1 (LFA–1). Cell 51, 813– 819 (1987).

    Article  CAS  Google Scholar 

  4. van de Stolpe, A. & van der Saag, P.T. Intercellular adhesion molecule–1. J. Mol. Med. 74, 13–33 (1996).

    Article  CAS  Google Scholar 

  5. Petruzzelli, L., Maduzia, L. & Springer, T.A. Activation of lymphocyte function–associated molecule–1 (CD11a/CD18) and Mac–1 (CD11b/CD18) mimicked by an antibody directed against CD18. J. Immunol. 155, 854–866 (1995).

    CAS  PubMed  Google Scholar 

  6. Ross, G.D., Cain, J.A. & Lachmann, P.J. Membrane complement receptor type three (CR3) has lectin–like properties analogous to bovine conglutinin and functions as a receptor for zymosan and rabbit erythrocytes as well as a receptor for iC3b. J. Immunol. 134, 3307– 3315 (1985).

    CAS  PubMed  Google Scholar 

  7. Graham, I.L., Gresham, H.D. & Brown, E.J. An immobile subset of plasma membrane CD11b/CD18 (Mac–1) is involved in phagocytosis of targets recognized by multiple receptors. J. Immunol. 142, 2352–2358 (1989).

    CAS  PubMed  Google Scholar 

  8. Isberg, R.R. Discrimination between intracellular uptake and surface adhesion of bacterial pathogens. Science 252, 934– 938 (1991).

    Article  CAS  Google Scholar 

  9. Tuomanen, E.I. in Leukocyte Adhesion: Basic and Clinical aspects. Proceedings of the 6th Novo Nordisk Foundation Symposium "Leukocyte Adhesion", Copenhagen, Denmark (eds. Gahmberg, C.G., Mandrup–Poulson, T. & Wogensen Bach, L.) 297–306 (Elsevier Science Publishers B. V., Amsterdam, 1992).

    Google Scholar 

  10. Nathan, C. et al. Cytokine–induced respiratory burst of human neutrophils: dependence on extracellular matrix proteins and CD11/CD18 integrins. J. Cell. Biol. 109, 1341–1349 (1989).

    Article  CAS  Google Scholar 

  11. Berton, G., Yan, S. R., Fumagalli, L. & Lowell, C. A. Neutrophil activation by adhesion: mechanisms and pathophysiological implications. Int. J. Clin. Lab. Res. 26, 160– 177 (1996).

    Article  CAS  Google Scholar 

  12. Ledebur, H.C. & Parks, T.P. Transcriptional regulation of the intercellular adhesion molecule–1 gene by inflammatory cytokines in human endothelial cells. Essential roles of a variant NF–kappa B site and p65 homodimers. J. Biol. Chem. 270, 933–943 (1995).

    Article  CAS  Google Scholar 

  13. Cabanas, C. & Hogg, N. Ligand intercellular adhesion molecule 1 has a necessary role in activation of integrin lymphocyte function–associated molecule 1. Proc. Natl. Acad. Sci. USA 90, 5838–5842 (1993).

    Article  CAS  Google Scholar 

  14. Leucocyte Typing V (eds. Schlossmann, S. F. et al.) 1548–1587 (Oxford University Press, Oxford, 1995).

  15. Diamond, M.S., Garcia–Aguilar, J., Bickford, J.K., Corbi, A.L. & Springer, T.A. The I domain is a major recognition site on the leukocyte integrin Mac–1 (CD11b/CD18) for four distinct adhesion ligands. J. Cell. Biol. 120, 1031–1043 (1993).

    Article  CAS  Google Scholar 

  16. Blackmore, T.K., Fischetti, V.A., Sadlon, H.M. & Gordon, D.L. M protein of group A streptococcus binds to the seventh short consensus repeat of human complement factor H. Infect. Immun. 66, 1427–1431 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Schmidt, K.H. et al. Susceptibility of chicken embryos to group A streptococci: correlation with fibrinogen binding. FEMS Immunol. Med. Microbiol. 7, 231–240 (1993).

    Article  CAS  Google Scholar 

  18. Verhoef, J., Peterson, P.K. & Quie, P.G. Kinetics of staphylococcal opsonization, attachment, ingestion and killing by human polymorphnuclear leukocytes: a quantitative assay using 3H Thymidine labeled bacteria. J. Immunol. Methods 14, 303–311 (1977).

    Article  CAS  Google Scholar 

  19. Mayer, C.L., Diamond, R.D. & Edwards, J.J.E. Recognition of binding sites on Candida albicans by monoclonal antibodies to human leucocyte antigens. Infect. Immun. 58, 3765–3769 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Rozdzinski, E. et al. Inhibition of leukocyte–endothelial cell interactions and inflammation by peptides from a bacterial adhesin which mimic coagulation factor X. J. Clin. Invest. 95, 1078– 1085 (1995).

    Article  CAS  Google Scholar 

  21. Van Seventer, G.A., Shimizu, Y., Horgan, K.J. & Shaw, S. The LFA–1 ligand ICAM–1 provides an important costimulatory signal for T cell receptor–mediated activation of resting T cells. J. Immunol. 144, 4579–4586 (1990).

    CAS  Google Scholar 

  22. Podbielski, A., Schnitzler, N., Beyhs, P. & Boyle, M.D. M–related protein (Mrp) contributes to group A streptococcal resistance to phagocytosis by human granulocytes. Mol. Microbiol. 19, 429–441 (1996).

    Article  CAS  Google Scholar 

  23. Kühnemund, O., Schumacher, F., Casaretto, M., Holm, S.E. & Lütticken, R. Estimation of type–specific anti–streptococcal M protein antibodies with biotinylated peptides in human sera. APMIS 106, 288– 292 (1998).

    Article  Google Scholar 

  24. Baltimore, R.S., Kasper, D.L., Baker, C.J. & Goroff, D.K. Antigenic specificity of opsonophagocytic antibodies in rabbit anti–sera to Group B Streptococci. J. Immunol. 118, 673–678 (1977).

    CAS  PubMed  Google Scholar 

  25. Salvadori, L.G., Blake, M.S., McCarty, M., Tai, J.Y. & Zabriskie, J.B. Group A Streptococcus–liposome ELISA antibody titers to Group A polysaccharide and opsonophagocytic capabilities of the antibodies. J. Infect. Dis. 171, 593– 600 (1994).

    Article  Google Scholar 

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Acknowledgements

We thank R. Holland for technical assistance. We are grateful to O. Kühnemund for testing for anti–M antibodies and to C.R. Jr. Cooper for critical reading of the manuscript.

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  1. Norbert Schnitzler

    Present address: Bundesministerium für Gesundheit, D–53108, Bonn>, Germany

Authors and Affiliations

  1. Institute of Medical Immunology, University Hospital, RWTH Aachen, Aachen, D–52057, Germany

    Norbert Schnitzler, Rudolf Lütticken & Klaus G. Schweizer

  2. Institute of Medical Microbiology and National Reference Center for Streptococci, University Hospital, RWTH Aachen, Aachen, D–52057, Germany

    Norbert Schnitzler, Gerhard Haase, Rudolf Lütticken & Klaus G. Schweizer

  3. Department of Medical Microbiology, University Hospital Ulm, Ulm, D–89081, Germany

    Andreas Podbielski

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Correspondence to Gerhard Haase.

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Schnitzler, N., Haase, G., Podbielski, A. et al. A co-stimulatory signal through ICAM-β2 integrin-binding potentiates neutrophil phagocytosis. Nat Med 5, 231–235 (1999). https://doi.org/10.1038/5597

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