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Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis

Abstract

A growing body of evidence indicates that resolution of acute inflammation is an active process1,2. Resolvins are a new family of lipid mediators enzymatically generated within resolution networks that possess unique and specific functions to orchestrate catabasis, the phase in which disease declines2,3. Resolvin D2 (RvD2) was originally identified in resolving exudates, yet its individual contribution in resolution remained to be elucidated. Here, we establish RvD2’s potent stereoselective actions in reducing excessive neutrophil trafficking to inflammatory loci. RvD2 decreased leukocyte–endothelial interactions in vivo by endothelial-dependent nitric oxide production, and by direct modulation of leukocyte adhesion receptor expression. In mice with microbial sepsis initiated by caecal ligation and puncture, RvD2 sharply decreased both local and systemic bacterial burden, excessive cytokine production and neutrophil recruitment, while increasing peritoneal mononuclear cells and macrophage phagocytosis. These multi-level pro-resolving actions of RvD2 translate to increased survival from sepsis induced by caecal ligation and puncture and surgery. Together, these results identify RvD2 as a potent endogenous regulator of excessive inflammatory responses that acts via multiple cellular targets to stimulate resolution and preserve immune vigilance.

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Figure 1: Stereochemical assignment, biosynthesis and total organic synthesis of RvD2.
Figure 2: RvD2 potently reduces leukocyte–endothelial interactions to reduce microbial peritonitis.
Figure 3: Modulation of leukocyte trafficking by RvD2 is nitric oxide dependent.
Figure 4: RvD2 reduces bacterial levels, systemic inflammation and enhances survival in microbial sepsis.

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References

  1. Gilroy, D. W., Lawrence, T., Perretti, M. & Rossi, A. G. Inflammatory resolution: new opportunities for drug discovery. Nature Rev. Drug Discov. 3, 401–416 (2004)

    Article  CAS  Google Scholar 

  2. Serhan, C. N., Chiang, N. & Van Dyke, T. E. Resolving inflammation: dual anti-inflammatory and pro-resolution lipid mediators. Nature Rev. Immunol. 8, 349–361 (2008)

    Article  CAS  Google Scholar 

  3. Serhan, C. N. et al. Resolvins: a family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025–1037 (2002)

    Article  CAS  Google Scholar 

  4. Weber, C., Zernecke, A. & Libby, P. The multifaceted contributions of leukocyte subsets to atherosclerosis: lessons from mouse models. Nature Rev. Immunol. 8, 802–815 (2008)

    Article  CAS  Google Scholar 

  5. Hotchkiss, R. S. & Karl, I. E. The pathophysiology and treatment of sepsis. N. Engl. J. Med. 348, 138–150 (2003)

    Article  CAS  Google Scholar 

  6. Shimizu, T. Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu. Rev. Pharmacol. Toxicol. 49, 123–150 (2009)

    Article  CAS  Google Scholar 

  7. Hong, S., Gronert, K., Devchand, P. R., Moussignac, R. L. & Serhan, C. N. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. J. Biol. Chem. 278, 14677–14687 (2003)

    Article  CAS  Google Scholar 

  8. Shimizu, T., Radmark, O. & Samuelsson, B. Enzyme with dual lipoxygenase activities catalyzes leukotriene A4 synthesis from arachidonic acid. Proc. Natl Acad. Sci. USA 81, 689–693 (1984)

    Article  CAS  ADS  Google Scholar 

  9. Rodriguez, A. R. & Spur, B. W. First total synthesis of 7(S),16(R),17(S)-Resolvin D2, a potent anti-inflammatory lipid mediator. Tetrahedr. Lett. 45, 8717–8720 (2004)

    Article  CAS  Google Scholar 

  10. Prescott, S. M., Zimmerman, G. A., Stafforini, D. M. & McIntyre, T. M. Platelet-activating factor and related lipid mediators. Annu. Rev. Biochem. 69, 419–445 (2000)

    Article  CAS  Google Scholar 

  11. Cooper, D., Norling, L. V. & Perretti, M. Novel insights into the inhibitory effects of Galectin-1 on neutrophil recruitment under flow. J. Leukoc. Biol. 83, 1459–1466 (2008)

    Article  CAS  Google Scholar 

  12. Rittirsch, D. et al. Functional roles for C5a receptors in sepsis. Nature Med. 14, 551–557 (2008)

    Article  CAS  Google Scholar 

  13. Kubes, P., Suzuki, M. & Granger, D. N. Nitric oxide: an endogenous modulator of leukocyte adhesion. Proc. Natl Acad. Sci. USA 88, 4651–4655 (1991)

    Article  CAS  ADS  Google Scholar 

  14. Moncada, S. & Higgs, E. A. The discovery of nitric oxide and its role in vascular biology. Br. J. Pharmacol. 147 (Suppl. 1). S193–S201 (2006)

    Article  CAS  Google Scholar 

  15. Bucci, M. et al. Endothelial nitric oxide synthase activation is critical for vascular leakage during acute inflammation in vivo. Proc. Natl Acad. Sci. USA 102, 904–908 (2005)

    Article  CAS  ADS  Google Scholar 

  16. Paul-Clark, M. J., Van Cao, T., Moradi-Bidhendi, N., Cooper, D. & Gilroy, D. W. 15-epi-lipoxin A4-mediated induction of nitric oxide explains how aspirin inhibits acute inflammation. J. Exp. Med. 200, 69–78 (2004)

    Article  CAS  Google Scholar 

  17. Rittirsch, D., Huber-Lang, M. S., Flierl, M. A. & Ward, P. A. Immunodesign of experimental sepsis by cecal ligation and puncture. Nature Protocols 4, 31–36 (2009)

    Article  CAS  Google Scholar 

  18. Buras, J. A., Holzmann, B. & Sitkovsky, M. Animal models of sepsis: setting the stage. Nature Rev. Drug Discov. 4, 854–865 (2005)

    Article  CAS  Google Scholar 

  19. Singer, P. et al. Anti-inflammatory properties of omega-3 fatty acids in critical illness: novel mechanisms and an integrative perspective. Intensive Care Med. 34, 1580–1592 (2008)

    Article  CAS  Google Scholar 

  20. Farolan, L. R., Goto, M., Myers, T. F., Anderson, C. L. & Zeller, W. P. Perinatal nutrition enriched with omega-3 polyunsaturated fatty acids attenuates endotoxic shock in newborn rats. Shock 6, 263–266 (1996)

    Article  CAS  Google Scholar 

  21. Pluess, T. T. et al. Intravenous fish oil blunts the physiological response to endotoxin in healthy subjects. Intensive Care Med. 33, 789–797 (2007)

    Article  CAS  Google Scholar 

  22. Haworth, R. et al. The macrophage scavenger receptor type A is expressed by activated macrophages and protects the host against lethal endotoxic shock. J. Exp. Med. 186, 1431–1439 (1997)

    Article  CAS  Google Scholar 

  23. Litvak, V. et al. Function of C/EBPdelta in a regulatory circuit that discriminates between transient and persistent TLR4-induced signals. Nature Immunol. 10, 437–443 (2009)

    Article  CAS  Google Scholar 

  24. Mosser, D. M. & Edwards, J. P. Exploring the full spectrum of macrophage activation. Nature Rev. Immunol. 8, 958–969 (2008)

    Article  CAS  Google Scholar 

  25. Flierl, M. A. et al. Adverse functions of IL-17A in experimental sepsis. FASEB J. 22, 2198–2205 (2008)

    Article  CAS  Google Scholar 

  26. Souza, D. G. et al. The required role of endogenously produced lipoxin A4 and annexin-1 for the production of IL-10 and inflammatory hyporesponsiveness in mice. J. Immunol. 179, 8533–8543 (2007)

    Article  CAS  Google Scholar 

  27. Osuchowski, M. F., Welch, K., Siddiqui, J. & Remick, D. G. Circulating cytokine/inhibitor profiles reshape the understanding of the SIRS/CARS continuum in sepsis and predict mortality. J. Immunol. 177, 1967–1974 (2006)

    Article  CAS  Google Scholar 

  28. Huang, X. et al. PD-1 expression by macrophages plays a pathologic role in altering microbial clearance and the innate inflammatory response to sepsis. Proc. Natl Acad. Sci. USA 106, 6303–6308 (2009)

    Article  CAS  ADS  Google Scholar 

  29. Dombrovskiy, V. Y., Martin, A. A., Sunderram, J. & Paz, H. L. Rapid increase in hospitalization and mortality rates for severe sepsis in the United States: a trend analysis from 1993 to 2003. Crit. Care Med. 35, 1244–1250 (2007)

    Article  Google Scholar 

  30. Chatterjee, B. E. et al. Annexin 1-deficient neutrophils exhibit enhanced transmigration in vivo and increased responsiveness in vitro. J. Leukoc. Biol. 78, 639–646 (2005)

    Article  CAS  Google Scholar 

  31. Serhan, C. N., Lu, Y., Hong, S. & Yang, R. Mediator lipidomics: search algorithms for eicosanoids, resolvins, and protectins. Methods Enzymol. 432, 275–317 (2007)

    Article  CAS  Google Scholar 

  32. Takano, T., Clish, C. B., Gronert, K., Petasis, N. & Serhan, C. N. Neutrophil-mediated changes in vascular permeability are inhibited by topical application of aspirin-triggered 15-epi-lipoxin A4 and novel lipoxin B4 stable analogues. J. Clin. Invest. 101, 819–826 (1998)

    Article  CAS  Google Scholar 

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Acknowledgements

We acknowledge support from National Institutes of Health grants GM-38765 and P50-DE016191 (C.N.S.), Welcome Trust Programme grant 086867/Z/08/Z (R.J.F. and M.P.) and Project grant 085903/Z/08 (R.J.F.) and Arthritis Research Campaign UK fellowships 18445 and 18103 (to L.V.N. and D.C., respectively). M.S. received a National Research Service Award from the NHLBI (HL087526). We thank J. W. Winkler and J. Uddin for work related to RvD2 synthesis, P. Pillai, K. Martinod, G. Fredman and J. Dalli for technical assistance, and M. H. Small for assistance with the manuscript. We also thank B. Schmidt for histopathology, Children’s Hospital Boston.

Author Contributions M.S. and L.V.N. designed and carried out experiments, analysed data and wrote the manuscript; L.S., R.Y. and D.C. carried out experiments and analysed data; N.A.P. synthesized RvD2; R.J.F. and M.P. designed experiments, analysed data and contributed to the manuscript; C.N.S. planned the project, designed experiments, analysed data and wrote the manuscript.

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Correspondence to Charles N. Serhan.

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Competing interests

[Competing Interests: The resolvins are biotemplates for stable analogues. Patents on these are awarded and assigned to Brigham and Women’s Hospital, C.N.S. is inventor. These analogue patents are licensed for clinical development.]

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11 with Legends, Supplementary Methods and Supplementary References. (PDF 4216 kb)

Supplementary Movie 1

This file shows a time-lapse movie (approximately 1 min at double-speed) of leukocyte adhesion to a post-capillary venule, and emigration into the surrounding tissue following 1h of PAF (1 nM) superfusion. (MOV 3218 kb)

Supplementary Movie 2

This file shows a time-lapse movie (approximately 1 min at double-speed) of decreased leukocyte adhesion to a post-capillary venule, and emigration into the surrounding tissue following 2h of PAF (1 nM) plus 1h of RvD2 (1 nM) superfusion. (MOV 3289 kb)

Supplementary Movie 3

This file shows the remarkable difference in behaviour of vehicle (red) or RvD2 (100 ng i.v.; blue) treated mice 12h after CLP-induced sepsis. (MOV 5050 kb)

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Spite, M., Norling, L., Summers, L. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009). https://doi.org/10.1038/nature08541

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