Resolvin E1 and protectin D1 activate inflammation-resolution programmes

Abstract

Resolution of acute inflammation is an active process essential for appropriate host responses, tissue protection and the return to homeostasis1,2,3. During resolution, specific omega-3 polyunsaturated fatty-acid-derived mediators are generated within resolving exudates, including resolvin E1 (RvE1)4 and protectin D1 (PD1)5. It is thus important to pinpoint specific actions of RvE1 and PD1 in regulating tissue resolution. Here we report that RvE1 and PD1 in nanogram quantities promote phagocyte removal during acute inflammation by regulating leukocyte infiltration, increasing macrophage ingestion of apoptotic polymorphonuclear neutrophils in vivo and in vitro, and enhancing the appearance of phagocytes carrying engulfed zymosan in lymph nodes and spleen. In this tissue terrain, inhibition of either cyclooxygenase or lipoxygenases—pivotal enzymes in the temporal generation of both pro-inflammatory and pro-resolving mediators—caused a ‘resolution deficit’ that was rescued by RvE1, PD1 or aspirin-triggered lipoxin A4 analogue. Also, new resolution routes were identified that involve phagocytes traversing perinodal adipose tissues and non-apoptotic polymorphonuclear neutrophils carrying engulfed zymosan to lymph nodes. Together, these results identify new active components for postexudate resolution traffic, and demonstrate that RvE1 and PD1 are potent agonists for resolution of inflamed tissues.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Pro-resolving lipid mediators RvE1, PD1 and ATLa direct local phagocyte tissue flux.
Figure 2: RvE1 and PD1 increase macrophage phagocytic activity in vivo and in vitro.
Figure 3: RvE1 and PD1 enhance leukocytes carrying phagocytosed zymosan in lymph nodes and spleen.
Figure 4: Active removal of leukocytes from the inflammatory exudate.

References

  1. 1

    Serhan, C. N. & Savill, J. Resolution of inflammation: the beginning programs the end. Nature Immunol. 6, 1191–1197 (2005)

  2. 2

    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)

  3. 3

    Nathan, C. Points of control in inflammation. Nature 420, 846–852 (2002)

  4. 4

    Serhan, C. N. et al. Novel functional sets of lipid-derived mediators with antiinflammatory actions generated from omega-3 fatty acids via cyclooxygenase 2-nonsteroidal antiinflammatory drugs and transcellular processing. J. Exp. Med. 192, 1197–1204 (2000)

  5. 5

    Hong, S., Gronert, K., Devchand, P., 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)

  6. 6

    Levy, B. D., Clish, C. B., Schmidt, B., Gronert, K. & Serhan, C. N. Lipid mediator class switching during acute inflammation: signals in resolution. Nature Immunol. 2, 612–619 (2001)

  7. 7

    Maddox, J. F. & Serhan, C. N. Lipoxin A4 and B4 are potent stimuli for human monocyte migration and adhesion: selective inactivation by dehydrogenation and reduction. J. Exp. Med. 183, 137–146 (1996)

  8. 8

    Serhan, C. N. Special issue on lipoxins and aspirin-triggered lipoxins. Prostaglandins Leukot. Essent. Fatty Acids 73, 139–321 (2005)

  9. 9

    Arita, M. et al. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. J. Exp. Med. 201, 713–722 (2005)

  10. 10

    Serhan, C. N. et al. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihydroxy-containing docosatrienes. J. Immunol. 176, 1848–1859 (2006)

  11. 11

    Bazan, N. G. Cell survival matters: docosahexaenoic acid signaling, neuroprotection and photoreceptors. Trends Neurosci. 29, 263–271 (2006)

  12. 12

    Bannenberg, G. L. et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. J. Immunol. 174, 4345–4355 (2005)

  13. 13

    Cotran, R. S., Kumar, V. & Collins, T. Robbins Pathologic Basis of Disease (W. B. Saunders, Philadelphia, 1999)

  14. 14

    Savill, J., Dransfield, I., Gregory, C. & Haslett, C. A blast from the past: clearance of apoptotic cells regulates immune responses. Nature Rev. Immunol. 2, 965–975 (2002)

  15. 15

    Sawatzky, D. A., Willoughby, D. A., Colville-Nash, P. R. & Rossi, A. G. The involvement of the apoptosis-modulating proteins ERK 1/2, Bcl-xL and Bax in the resolution of acute inflammation in vivo. Am. J. Pathol. 168, 33–41 (2006)

  16. 16

    Rossi, A. G. et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nature Med. 12, 1056–1064 (2006)

  17. 17

    Reville, K., Crean, J. K., Vivers, S., Dransfield, I. & Godson, C. Lipoxin A4 redistributes myosin IIA and Cdc42 in macrophages: implications for phagocytosis of apoptotic leukocytes. J. Immunol. 176, 1878–1888 (2006)

  18. 18

    Freire-de-Lima, C. G. et al. Apoptotic cells, through transforming growth factor-beta, coordinately induce anti-inflammatory and suppress pro-inflammatory eicosanoid and NO synthesis in murine macrophages. J. Biol. Chem. 281, 38376–38384 (2006)

  19. 19

    Maderna, P., Yona, S., Perretti, M. & Godson, C. Modulation of phagocytosis of apoptotic neutrophils by supernatant from dexamethasone-treated macrophages and annexin-derived peptide Ac(2–26). J. Immunol. 174, 3727–3733 (2005)

  20. 20

    Liu, Y. et al. Glucocorticoids promote nonphlogistic phagocytosis of apoptotic leukocytes. J. Immunol. 162, 3639–3646 (1999)

  21. 21

    Vandivier, R. W., Henson, P. M. & Douglas, I. S. Burying the dead: the impact of failed apoptotic cell removal (efferocytosis) on chronic inflammatory lung disease. Chest 129, 1673–1682 (2006)

  22. 22

    Underhill, D. M. Macrophage recognition of zymosan particles. J. Endotoxin Res. 9, 176–180 (2003)

  23. 23

    Gilroy, D. W. et al. Inducible cycloxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999)

  24. 24

    Gronert, K. et al. A role for the mouse 12/15-lipoxygenase pathway in promoting epithelial wound healing and host defense. J. Biol. Chem. 280, 15267–15278 (2005)

  25. 25

    Sadik, C. D., Sies, H. & Schewe, T. Inhibition of 15-lipoxygenases by flavonoids: structure-activity relations and mode of action. Biochem. Pharmacol. 65, 773–781 (2003)

  26. 26

    Bellingan, G. J. et al. Adhesion molecule-dependent mechanisms regulate the rate of macrophage clearance during the resolution of peritoneal inflammation. J. Exp. Med. 196, 1515–1521 (2002)

  27. 27

    Cao, C., Lawrence, D. A., Strickland, D. K. & Zhang, L. A specific role of integrin Mac-1 in accelerated macrophage efflux to the lymphatics. Blood 106, 3234–3241 (2005)

  28. 28

    Pond, C. M. Adipose tissue and the immune system. Prostaglandins Leukot. Essent. Fatty Acids 73, 17–30 (2005)

  29. 29

    Wellen, K. E. & Hotamisligil, G. S. Inflammation, stress, and diabetes. J. Clin. Invest. 115, 1111–1119 (2005)

Download references

Acknowledgements

These studies were supported in part by the NIH (C.N.S.) and a Research Fellowship from the Deutsche Forschungsgemeinschaft (J.M.S.). We thank J. Kutok for discussion regarding immunohistology, G. Fredman for assistance with fluorescence-activated cell sorting (FACS) and S. Elangovan for technical support. We also thank L. Xu and K. Gotlinger for mass spectral analyses and M. Halm Small for manuscript preparation. We also acknowledge NIH support for the Organic Synthesis Core (NAP) of the NIH-supported P50 Center grant (C.N.S.).

Author Contributions C.N.S. planned the project, designed experiments, analysed data and wrote the manuscript; N.C. and J.M.S. designed and carried out experiments, analysed data, and wrote the manuscript; M.A. analysed and discussed data.

Author information

Correspondence to Charles N. Serhan.

Ethics declarations

Competing interests

The Brigham and Women’s Hospital is assigned patents on lipoxins and resolvins that are subjects of licensing agreements and consultant arrangements for C.N.S.

Supplementary information

Supplementary Information 1

This file contains Supplementary Figures S1- S10 with Legends and Supplementary Table S1. (PDF 3699 kb)

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Schwab, J., Chiang, N., Arita, M. et al. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007). https://doi.org/10.1038/nature05877

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.