Resolution of inflammation: the beginning programs the end

Abstract

Acute inflammation normally resolves by mechanisms that have remained somewhat elusive. Emerging evidence now suggests that an active, coordinated program of resolution initiates in the first few hours after an inflammatory response begins. After entering tissues, granulocytes promote the switch of arachidonic acid–derived prostaglandins and leukotrienes to lipoxins, which initiate the termination sequence. Neutrophil recruitment thus ceases and programmed death by apoptosis is engaged. These events coincide with the biosynthesis, from omega-3 polyunsaturated fatty acids, of resolvins and protectins, which critically shorten the period of neutrophil infiltration by initiating apoptosis. Consequently, apoptotic neutrophils undergo phagocytosis by macrophages, leading to neutrophil clearance and release of anti-inflammatory and reparative cytokines such as transforming growth factor-β1. The anti-inflammatory program ends with the departure of macrophages through the lymphatics. Understanding these and further details of the mechanism required for inflammation resolution may underpin the development of drugs that can resolve inflammatory processes in directed and controlled ways.

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Figure 1: Temporal events and programming in resolution of acute inflammation: the function of lipid-derived mediators.
Figure 2: Function of essential polyunsaturated fatty acids in the production of families of bioactive lipid mediators.
Figure 3: Regulation of macrophage activation by interaction with apoptotic cells.

References

  1. 1

    Majno, G. The Healing Hand: Man and Wound in the Ancient World (Harvard University Press, Cambridge, Massachusetts, 1975).

    Google Scholar 

  2. 2

    Gallin, J.I., Snyderman, R., Fearon, D.T., Haynes, B.F. & Nathan, C. Inflammation: Basic Principles and Clinical Correlates (Lippincott Williams & Wilkins, Philadelphia, 1999).

    Google Scholar 

  3. 3

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

    CAS  Article  Google Scholar 

  4. 4

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

    CAS  Article  Google Scholar 

  5. 5

    Lawrence, T., Willoughby, D.A. & Gilroy, D.W. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat. Rev. Immunol. 2, 787–795 (2002).

    CAS  Article  Google Scholar 

  6. 6

    Savill, J. Apoptosis in resolution of inflammation. J. Leukoc. Biol. 61, 375–380 (1997).

    CAS  Article  Google Scholar 

  7. 7

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

    CAS  Article  Google Scholar 

  8. 8

    Williams, T.J. & Peck, M.J. Role of prostaglandin-mediated vasodilatation in inflammation. Nature 270, 530–532 (1977).

    CAS  Article  Google Scholar 

  9. 9

    Pouliot, M., Fiset, M.E., Masse, M., Naccache, P.H. & Borgeat, P. Adenosine up-regulates cyclooxygenase-2 in human granulocytes: impact on the balance of eicosanoid generation. J. Immunol. 169, 5279–5286 (2002).

    Article  Google Scholar 

  10. 10

    Serhan, C.N. et al. Novel functional sets of lipid-derived mediators with anti-inflammatory actions generated from omega-3 fatty acids via cyclooxygenase2-nonsteroidal anti-inflammatory drugs and transcellular processing. J. Exp. Med. 192, 1197–1204 (2000).

    CAS  Article  Google Scholar 

  11. 11

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

    CAS  Article  Google Scholar 

  12. 12

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

    CAS  Article  Google Scholar 

  13. 13

    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).

    CAS  Article  Google Scholar 

  14. 14

    Marcheselli, V.L. et al. Novel docosanoids inhibit brain ischemia-reperfusion-mediated leukocyte infiltration and pro-inflammatory gene expression. J. Biol. Chem. 278, 43807–43817 (2003).

    CAS  Article  Google Scholar 

  15. 15

    Serhan, C.N. et al. Design of lipoxin A4 stable analogs that block transmigration and adhesion of human neutrophils. Biochemistry 34, 14609–14615 (1995).

    CAS  Article  Google Scholar 

  16. 16

    Chiang, N. et al. Leukotriene B4 receptor transgenic mice reveal novel protective roles for lipoxins and aspirin-triggered lipoxins in reperfusion. J. Clin. Invest. 104, 309–316 (1999).

    CAS  Article  Google Scholar 

  17. 17

    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).

    CAS  Article  Google Scholar 

  18. 18

    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).

    CAS  Article  Google Scholar 

  19. 19

    Godson, C. et al. Cutting edge: Lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. J. Immunol. 164, 1663–1667 (2000).

    CAS  Article  Google Scholar 

  20. 20

    Colgan, S.P., Serhan, C.N., Parkos, C.A., Delp-Archer, C. & Madara, J.L. Lipoxin A4 modulates transmigration of human neutrophils across intestinal epithelial monolayers. J. Clin. Invest. 92, 75–82 (1993).

    CAS  Article  Google Scholar 

  21. 21

    Lawrence, T., Bebien, M., Liu, G.Y., Nizet, V. & Karin, M. IKKα limits macrophage NF-kappaB activation and contributes to the resolution of inflammation. Nature 434, 1138–1143 (2005).

    CAS  Article  Google Scholar 

  22. 22

    Savill, J. Apoptosis in post-streptococcal glomerulonephritis. Kidney Int. 60, 1203–1214 (2001).

    CAS  Article  Google Scholar 

  23. 23

    Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation (Kegan, Paul, Trench and Trubner, London, 1893).

    Google Scholar 

  24. 24

    Hurley, J.V. in Acute inflammation (ed. Hurley, J.V.) 109–117 (Churchill Livingstone, London, 1983).

    Google Scholar 

  25. 25

    Newman, S.L., Henson, J.E. & Henson, P.M. Phagocytosis of senescent neutrophils by human monocyte-derived macrophages and rabbit inflammatory macrophages. J. Exp. Med. 156, 430–442 (1982).

    CAS  Article  Google Scholar 

  26. 26

    Savill, J.S., Wyllie, A.H., Henson, J.E., Walport, M.J. & Henson, P.M. Haslett, C. Macrophage phagocytosis of aging neutrophils in inflammation. Programmed cell death in the neutrophil leads to its recognition by macrophages. J. Clin. Invest. 83, 865–875 (1989).

    CAS  Article  Google Scholar 

  27. 27

    Bellingan, G.J. et al. In vivo fate of the inflammatory macrophage during the resolution of inflammation: Inflammatory macrophages do not die locally but emigrate to the draining lymph nodes. J. Immunol. 157, 2577–2585 (1996).

    CAS  PubMed  Google Scholar 

  28. 28

    Lee, A., Whyte, M.K. & Haslett, C. Inhibition of apoptosis and prolongation of neutrophil functional longevity by inflammatory mediators. J. Leukoc. Biol. 54, 283–288 (1993).

    CAS  Article  Google Scholar 

  29. 29

    Ward, C. et al. 1999. NK-κB activation is a critical regulator of human granulocyte apoptosis in vitro. J. Biol. Chem. 274, 4309 (1999).

    CAS  Article  Google Scholar 

  30. 30

    Jonsson, H., Allen, P. & Peng, S.L. Inflammatory arthritis requires Foxo3a to prevent Fas ligand-induced neutrophil apoptosis. Nat. Med. (2005).

  31. 31

    Brown, S.B. Savill, J. Phagocytosis triggers macrophage release of Fas-ligand and induces apoptosis of bystander leukocytes. J. Immunol. 162, 480–485 (1999).

    CAS  Google Scholar 

  32. 32

    Meagher, L.C., Cousin, J.M. & Seckl, J.R. Haslett, C. Opposing effects of glucocorticoids on the rate of apoptosis in neutrophilic and eosinophilic granulocytes. J. Immunol. 156, 4422 (1996).

    CAS  Google Scholar 

  33. 33

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

    CAS  Google Scholar 

  34. 34

    Giles, K.M. et al. Glucocorticoid augmentation of macrophage capacity for phagocytosis of apoptotic cells is associated with reduced p130Cas expression, loss of paxillin/pyk2 phosphorylation and high levels of active Rac. J. Immunol. 167, 976–986 (2001).

    CAS  Article  Google Scholar 

  35. 35

    Voll, R.E. et al. Immunosuppressive effects of apoptotic cells. Nature 390, 350–351 (1997).

    CAS  Article  Google Scholar 

  36. 36

    Fadok, V. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGF-β, PGE2 and PAF. J. Clin. Invest. 101, 890–898 (1998).

    CAS  Article  Google Scholar 

  37. 37

    Huynh, M-L.N., Fadok, V.A., Henson, P.M. Phosphatidylserine-dependent ingestion of apoptotic cells promoted TGF-β1 secretion and the resolution of inflammation. J. Clin. Invest. 109, 41–50 (2002).

    CAS  Article  Google Scholar 

  38. 38

    Lucas, M., Stuart, L.M., Savill, J. & Lacy-Hulbert, A. Apoptotic cells and innate immune stimuli combine to regulate macrophage cytokine secretion. J. Immunol. 171, 2610–2615 (2003).

    CAS  Article  Google Scholar 

  39. 39

    Byrne, A. & Reen, D.J. Lipopolysaccharide induces rapid production of IL-10 by monocytes in the presence of apoptotic neutrophils. J. Immunol. 168, 1968–1997 (2002).

    CAS  Article  Google Scholar 

  40. 40

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

    CAS  Article  Google Scholar 

  41. 41

    Lauber, K., Blumenthal, S.G., Waibel, M. & Wesselborg, S. Clearance of apoptotic cells: Getting rid of the corpses. Mol. Cell 14, 277–287 (2004).

    CAS  Article  Google Scholar 

  42. 42

    Fadok, V. et al. A receptor for phosphatidylserine-specific clearance of apoptotic cells. Nature 405, 85–90 (2000).

    CAS  Article  Google Scholar 

  43. 43

    Bose, J. et al. The phosphatidylserine receptor has essential functions during embryogenesis but not in apoptotic cell removal. J. Biol. 3, 15 (2004).

    Article  Google Scholar 

  44. 44

    Duffield, J.S., Ware, C.F., Ryffel, B. & Savill, J. Suppression by apoptotic cells defines tumour necrosis factor-mediated induction of glomerular mesangial cell apoptosis by activated macrophages. Am. J. Pathol. 159, 1397–1404 (2001).

    CAS  Article  Google Scholar 

  45. 45

    Golpon, H.A. et al. Life after corpse engulfment: phagocytosis of apoptotic cells leads to VEGF secretion and cell growth. FASEB J. 18, 1716–1718 (2004).

    CAS  Article  Google Scholar 

  46. 46

    Ryoo, H.D., Gorenc, T. & Steller, H. Apoptotic cells can induce compensatory cell proliferation through the JNK and the wingless signaling pathways. Dev. Cell 7, 491–501 (2004).

    CAS  Article  Google Scholar 

  47. 47

    Gilmour, J.S. et al. Local amplification of glucocorticoids by 11β-hydroxysteroid dehydrogenase type 1 promotes macrophage phagocytosis of apoptotic leukocytes. J. Immunol. (in the press).

  48. 48

    Ren, Y. et al. Non-phlogistic clearance of late apoptotic neutrophils by macrophages: Efficient phagocytosis independent of β2 integrins. J. Immunol. 166, 4743–4750 (2001).

    CAS  Article  Google Scholar 

  49. 49

    Erwig, L.P., Kluth, D.C. & Walsh, G.M. Rees, A.J. Initial cytokine exposure determines function of macrophages and renders them unresponsive to other cytokines. J. Immunol. 161, 1983–1988 (1998).

    CAS  PubMed  Google Scholar 

  50. 50

    Erwig, L.P., Stewart, K. & Rees, A.J. Macrophages from inflamed but not normal glomeruli are unresponsive to anti-inflammatory cytokines. Am. J. Pathol. 156, 295–301 (2000).

    CAS  Article  Google Scholar 

  51. 51

    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).

    CAS  Article  Google Scholar 

  52. 52

    Burr, G.O. & Burr, M.M. A new deficiency disease produced by the rigid exclusion of fat from the diet. J. Biol. Chem. 82, 345–367 (1929).

    CAS  Google Scholar 

  53. 53

    GISSI-Prevenzione Investigators. Dietary supplementation with n-3 polyunsaturated fatty acids and vitamin E after myocardial infarction: results of the GISSI-Prevenzione trial. Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico. Lancet 354, 447–455 (1999).

  54. 54

    Marchioli, R. et al. Early protection against sudden death by n-3 polyunsaturated fatty acids after myocardial infarction: time-course analysis of the results of the Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation 105, 1897–1903 (2002).

    CAS  Article  Google Scholar 

  55. 55

    Gilroy, D.W. & Perretti, M. Aspirin and steroids: new mechanistic findings and avenues for drug discovery. Curr. Opin. Pharmacol. 5, 405–411 (2005).

    CAS  Article  Google Scholar 

  56. 56

    Maderna, P., Yona, S., Perretti, M. & Godson, C. Modulation of phagocytosis of apoptotic neutrophils by supernatant from Dexamethasone-treated macrophages and annexin-dervied peptide Ac2–261. J. Immunol. 174, 3727–3733 (2005).

    CAS  Article  Google Scholar 

  57. 57

    Ward, C. et al. Prostaglandin D2 and its metabolites induce caspase-dependent granulocyte apoptosis that is mediated via inhibition of IκBα degradation using a peroxisome proliferator-activated receptor-γ-independent mechanism. J. Immunol. 168, 6232–6243 (2002).

    CAS  Article  Google Scholar 

  58. 58

    Arita, M. et al. Resolvin E1, a novel endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against TNBS-induced colitis. Proc. Natl. Acad. Sci. USA 102, 7671–7676 (2005).

    CAS  Article  Google Scholar 

  59. 59

    Wallace, J.L. & Fiorucci, S. A magic bullet for mucosal protection...and aspirin is the trigger! Trends Pharmacol. Sci. 24, 323–326 (2003).

    CAS  Article  Google Scholar 

  60. 60

    Fukunaga, K., Kohli, P., Bonnans, C., Fredenburgh, L.E. & Levy, B.D. Cyclooxygenase 2 plays a pivotal role in the resolution of acute lung injury. J. Immunol. 174, 5033–5039 (2005).

    CAS  Article  Google Scholar 

  61. 61

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

    CAS  Article  Google Scholar 

  62. 62

    Clària, J. & Serhan, C.N. Aspirin triggers previously undescribed bioactive eicosanoids by human endothelial cell-leukocyte interactions. Proc. Natl. Acad. Sci. USA 92, 9475–9479 (1995).

    Article  Google Scholar 

  63. 63

    Schottelius, A.J. et al. An aspirin-triggered lipoxin A4 stable analog displays a unique topical anti-inflammatory profile. J. Immunol. 169, 7063–7070 (2002).

    CAS  Article  Google Scholar 

  64. 64

    Fiorucci, S. et al. A beta-oxidation-resistant lipoxin A4 analog treats hapten-induced colitis by attenuating inflammation and immune dysfunction. Proc. Natl. Acad. Sci. USA 101, 15736–15741 (2004).

    CAS  Article  Google Scholar 

  65. 65

    Karp, C.L. et al. Defective lipoxin-mediated anti-inflammatory activity in the cystic fibrosis airway. Nat. Immunol. 5, 388–392 (2004).

    CAS  Article  Google Scholar 

  66. 66

    Mitchell, S. et al. Lipoxins, aspirin-triggered epi-lipoxins, lipoxin stable analogues, and the resolution of inflammation: stimulation of macrophage phagocytosis of apoptotic neutrophils in vivo. J. Am. Soc. Nephrol. 13, 2497–2507 (2002).

    CAS  Article  Google Scholar 

  67. 67

    Taylor, P.R. et al. A hierarchical role for classical pathway complement proteins in the clearance of apoptotic cells in vivo. J. Exp. Med. 192, 359–366 (2000).

    CAS  Article  Google Scholar 

  68. 68

    Hanayama, R. et al. Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice. Science 304, 1147–1150 (2004).

    CAS  Article  Google Scholar 

  69. 69

    Devitt, A. et al. Persistence of apoptotic cells without autimmune disease or inflammation in CD14−/− mice. J. Cell Biol. 167, 1161–1170 (2004).

    CAS  Article  Google Scholar 

  70. 70

    Stuart, L.M., Takahashi, K., Shi, L., Savill, J. & Ezekowitz, R.A.B. Mannose-binding lectin-deficient mice display defective apoptotic cell clearance but no autoimmune phenotyope. J. Immunol. 174, 3220–3226 (2005).

    CAS  Article  Google Scholar 

  71. 71

    Samuelsson, B., Dahlén, S.E., Lindgren, J.Å., Rouzer, C.A. & Serhan, C.N. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science 237, 1171–1176 (1987).

    CAS  Article  Google Scholar 

  72. 72

    Funk, C.D. Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science 294, 1871–1875 (2001).

    CAS  Article  Google Scholar 

  73. 73

    Capdevila, J.H., Falck, J.R., Dishman, E. & Karara, A. in Arachidonate Related Lipid Mediators (eds. Murphy, R.C. & Fitzpatrick, F.A.) 385–394 (Academic, San Diego, 1990).

    Google Scholar 

  74. 74

    Node, K. et al. Anti-inflammatory properties of cytochrome P450 epoxygenase-derived eicosanoids. Science 285, 1276–1279 (1999).

    CAS  Article  Google Scholar 

  75. 75

    Mukherjee, P.K., Marcheselli, V.L., Serhan, C.N. & Bazan, N.G. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc. Natl. Acad. Sci. USA 101, 8491–8496 (2004).

    CAS  Article  Google Scholar 

  76. 76

    Hughes, J.A. & Savill, J. Apoptosis in glomerulonephritis. Cur. Opn. Neph. & Hyper. 14, 389–395 (2005).

    Article  Google Scholar 

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Acknowledgements

We thank M.H. Small, C. Gilchrist and C. Law for assistance in manuscript preparation, and K. Gotlinger for assistance with the illustrations. Supported by the National Institutes of Health (P50-DE016191 and GM38765 to C.N.S.), the Wellcome Trust (064487 to J.S.) and the Medical Research Council (J.S.).

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Correspondence to Charles N Serhan.

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Serhan, C., Savill, J. Resolution of inflammation: the beginning programs the end. Nat Immunol 6, 1191–1197 (2005). https://doi.org/10.1038/ni1276

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