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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.

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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.

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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

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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

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  1. Nicole C Kaneider
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  2. Anika Agarwal
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Correspondence to Athan Kuliopulos.

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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)

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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

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