Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Reversing systemic inflammatory response syndrome with chemokine receptor pepducins

Nature Medicine volume 11, pages 661–665 (2005)Cite this article

Abstract

We describe a new therapeutic approach for the treatment of lethal sepsis using cell-penetrating lipopeptides—termed pepducins—that target either individual or multiple chemokine receptors. Interleukin-8 (IL-8), a ligand for the CXCR1 and CXCR2 receptors, is the most potent endogenous proinflammatory chemokine in sepsis. IL-8 levels rise in blood and lung fluids to activate neutrophils and other cells, and correlate with shock, lung injury and high mortality1,2,3,4,5. We show that pepducins derived from either the i1 or i3 intracellular loops of CXCR1 and CXCR2 prevent the IL-8 response of both receptors and reverse the lethal sequelae of sepsis, including disseminated intravascular coagulation and multi-organ failure in mice. Conversely, pepducins selective for CXCR4 cause a massive leukocytosis that does not affect survival. CXCR1 and CXCR2 pepducins conferred nearly 100% survival even when treatment was postponed, suggesting that our approach might be beneficial in the setting of advanced disease.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Rent or buy this article

Get just this article for as long as you need it

$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Figure 1: CXCR1, CXCR2 and CXCR4 i1-loop and i3-loop pepducins inhibit Ca2+ mobilization in human neutrophils.
Figure 2: CXCR1 and CXCR2 and CXCR4 pepducins inhibit chemotaxis and modulate leukocyte homeostasis of human and mouse neutrophils.
Figure 3: Effect of immediate versus delayed treatment with CXCR1 and CXCR2 pepducins on survival of wild-type mice subjected to CLP.
Figure 4: Pepducin treatment reverses the lethal sequelae of sepsis, including lung and liver damage and disseminated intravascular coagulation in mice.

References

  1. Hack, C.E. et al. Interleukin-8 in sepsis: relation to shock and inflammatory mediators. Infect. Immun. 60, 2835–2842 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Friedland, J.S. et al. Prolonged elevation of interleukin-8 and interleukin-6 concentrations in plasma and of leukocyte interleukin-8 mRNA levels during septicemic and localized Pseudomonas pseudomallei infection. Infect. Immun. 60, 2402–2408 (1992).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Miller, E.J. et al. Elevated levels of NAP-1/interleukin-8 are present in the airspaces of patients with the adult respiratory distress syndrome and are associated with increased mortality. Am. Rev. Respir. Dis. 146, 427–432 (1992).

    Article  CAS  Google Scholar 

  4. Endo, S. et al. Plasma interleukin 8 and polymorphonuclear leukocyte elastase concentrations in patients with septic shock. J. Inflamm. 454, 136–142 (1995).

    Google Scholar 

  5. Redl, H. et al. Plasma neutrophil-activating peptide-1/interleukin-8 and neutrophil elastase in a primate bacteremia model. J. Infect. Dis. 164, 383–388 (1991).

    Article  CAS  Google Scholar 

  6. Riedemann, N.C., Guo, R.F. & Ward, P.A. Novel strategies for the treatment of sepsis. Nat. Med. 9, 517–524 (2003).

    Article  CAS  Google Scholar 

  7. Wheeler, A.P. & Bernard, G.R. Treating patients with severe sepsis. N. Engl. J. Med. 340, 207–214 (1999).

    Article  CAS  Google Scholar 

  8. Bone, R.C. Toward a theory regarding the pathogenesis of the systemic inflammatory response syndrome: what we do and do not know about cytokine regulation. Crit. Care Med. 24, 163–172 (1996).

    Article  CAS  Google Scholar 

  9. Nichols, R.L. et al. Risk of infection after penetrating abdominal trauma. N. Engl. J. Med. 311, 1065–1070 (1984).

    Article  CAS  Google Scholar 

  10. Dinarello, C.A., Gelfand, J.A. & Wolff, S.M. Anticytokine strategies in the treatment of the systemic inflammatory response syndrome. JAMA 269, 1829–1835 (1993).

    Article  CAS  Google Scholar 

  11. Matsukawa, A., Hogaboam, C.M., Lukacs, N.W. & Kunkel, S.L. Chemokines and innate immunity. Rev. Immunogenet. 2, 339–358 (2000).

    CAS  PubMed  Google Scholar 

  12. Taub, D.D. The voodoo that they do so well. Cytokine Growth Factor Rev. 7, 355–376 (1996).

    Article  CAS  Google Scholar 

  13. Ness, T.E., Hogaboam, C.M., Strieter, R.M. & Kunkel, S.L. Immunomodulatory role of CXCR2 during experimental septic peritonitis. J. Immunol. 171, 3775–3784 (2003).

    Article  CAS  Google Scholar 

  14. Gando, S. et al. Combined activation of coagulation and inflammation has an important role in multiple organ dysfunction and poor outcome after severe trauma. Thromb. Haemost. 88, 943–949 (2002).

    Article  CAS  Google Scholar 

  15. Levi, M. & Cate, H.T. Disseminated intravascular coagulation. N. Engl. J. Med. 341, 586–592 (1999).

    Article  CAS  Google Scholar 

  16. Allen, C.D. et al. Germinal center dark and light zone organization is mediated by CXCR4 and CXCR5. Nat. Immunol. 5, 943–952 (2004).

    Article  CAS  Google Scholar 

  17. Martin, C. et al. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity 19, 583–593 (2003).

    Article  CAS  Google Scholar 

  18. Darash-Yahana, M. et al. Role of high expression levels of CXCR4 in tumor growth, vascularization, and metastasis. FASEB J. 18, 1240–1242 (2004).

    Article  CAS  Google Scholar 

  19. Bertini, R. et al. Noncompetitive allosteric inhibitors of the inflammatory chemokine receptors CXCR1 and CXCR2: prevention of reperfusion injury. Proc. Natl. Acad. Sci. USA 101, 11791–11796 (2004).

    Article  CAS  Google Scholar 

  20. Lomas-Neira, J.L., Chung, C.S., Grutkoski, P.S., Miller, E.J. & Ayala, A. CXCR2 inhibition suppresses hemorrhage-induced priming for acute lung injury in mice. J. Leukoc. Biol. 76, 58–64 (2004).

    Article  CAS  Google Scholar 

  21. Covic, L., Gresser, A.L., Talavera, J., Swift, S. & Kuliopulos, A. Activation and inhibition of G protein-coupled receptors by cell-penetrating membrane-tethered peptides. Proc. Natl. Acad. Sci. USA 99, 643–648 (2002).

    Article  CAS  Google Scholar 

  22. Covic, L., Misra, M., Badar, J., Singh, C. & Kuliopulos, A. Pepducin-based intervention of thrombin receptor signaling and systemic platelet activation. Nat. Med. 8, 1161–1165 (2002).

    Article  CAS  Google Scholar 

  23. Boire, A. et al. PAR1 is a Matrix metalloprotease-1 receptor that promotes invasion and tumorigenesis of breast cancer cells. Cell 120, 303–313 (2005).

    Article  CAS  Google Scholar 

  24. Suratt, B.T. et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood 104, 565–571 (2004).

    Article  CAS  Google Scholar 

  25. Bonecchi, R. et al. Induction of functional IL-8 receptors by IL-4 and IL-13 in human monocytes. J. Immunol. 164, 3862–3869 (2000).

    Article  CAS  Google Scholar 

  26. Cacalano, G. et al. Neutrophil and B cell expansion in mice that lack the murine IL-8 receptor homolog. Science 265, 682–684 (1994).

    Article  CAS  Google Scholar 

  27. Skelton, N.J., Quan, C., Reilly, D. & Lowman, H. Structure of a CXC chemokine-receptor fragment in complex with interleukin-8. Structure Fold Des. 7, 157–168 (1999).

    Article  CAS  Google Scholar 

  28. Kuliopulos, A. & Walsh, C.T. Production, purification, and cleavage of tandem repeats of recombinant peptides. J. Am. Chem. Soc. 116, 4599–4607 (1994).

    Article  CAS  Google Scholar 

  29. Wiedermann, C.J., Niedermuhlbichler, M. & Braunsteiner, H. Priming of polymorphonuclear neutrophils by atrial natriuretic peptide in vitro. J. Clin. Invest. 89, 1580–1586 (1992).

    Article  CAS  Google Scholar 

  30. Covic, L., Gresser, A.L. & Kuliopulos, A. Biphasic kinetics of activation and signaling for PAR1 and PAR4 thrombin receptors in platelets. Biochemistry 39, 5458–5467 (2000).

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank L. Covic for advice and comments on the manuscript, J. Yu for construction of stable CXCR1/2/4 HEK cell lines and lipidation of pepducins, B. Tchernychev for development of pepducin dosages and delivery, and S. Swift and S. Jacques for help in production of recombinant SDF-1α and IL-8. The support from the FWF Austrian Science Foundation (Erwin Schrodinger Fellowship

Author information

Authors and Affiliations

  1. New England Medical Center and Departments of Medicine and Biochemistry, Molecular Oncology Research Institute, Tufts University School of Medicine, 750 Washington Street, Boston, 02111, Massachusetts, USA

    Nicole C Kaneider, Anika Agarwal, Andrew J Leger & Athan Kuliopulos

Authors
  1. Nicole C Kaneider
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anika Agarwal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Andrew J Leger
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Athan Kuliopulos
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Athan Kuliopulos.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

Chemokine pepducins are selective for their cognate receptors. (PDF 106 kb)

Supplementary Fig. 2

Effect of CXCR1/2 pepducins on eupathy in septic mice. (PDF 178 kb)

Supplementary Fig. 3

CXCR1/2 pepducins protect against lung injury and inhibit IL-8-dependent activity of several cell types. (PDF 370 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Kaneider, N., Agarwal, A., Leger, A. et al. Reversing systemic inflammatory response syndrome with chemokine receptor pepducins. Nat Med 11, 661–665 (2005). https://doi.org/10.1038/nm1245

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nm1245

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing