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Anti-inflammatory lipid mediators and insights into the resolution of inflammation

Key Points

  • The resolution of inflammation is a highly controlled and coordinated process that involves the suppression of pro-inflammatory gene expression, and of leukocyte migration and activation, followed by inflammatory-cell clearance by apoptosis and phagocytosis.

  • New endogenous anti-inflammatory mediators, such as cyclopentenone prostaglandins (cyPGs) and lipoxins, might regulate the resolution of inflammation.

  • Lipoxins are early braking signals for the inflammatory response; they inhibit neutrophil migration and activation, but promote the recruitment of monocytes and the phagocytic clearance of apoptotic cells by monocyte-derived macrophages.

  • Cyclopentenone prostaglandins are potent suppressors of macrophage activation and specifically target the pro-inflammatory nuclear factor-κB (NF-κB) signalling pathways.

  • NF-κB regulates the expression of pro-inflammatory and anti-apoptotic genes; therefore, cyPGs can mediate the resolution of inflammation through the suppression of pro-inflammatory gene expression and the promotion of leukocyte apoptosis.

  • Both lipoxins and cyPGs have shown therapeutic promise in several animal models of inflammatory and autoimmune diseases. Therapeutic agents based on these new anti-inflammatory lipid mediators might offer a new approach to the treatment of chronic inflammatory diseases.

Abstract

The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.

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Figure 1: Cardinal signs of inflammation.
Figure 2: Theoretical time course of acute inflammation and associated mediators.
Figure 3: The two faces of phagocytosis.
Figure 4: NF-κB activation in response to pro-inflammatory stimuli.
Figure 5: Hypothetical model of an alternative anti-inflammatory pathway of NF-κB activation.

References

  1. Florey, H. W. General Pathology (Lloyd–Luke, London, 1970).

    Google Scholar 

  2. Majno, G. The Healing Hand: Man and Wound in the Ancient World (Harvard University Press, Cambridge, Massachusetts, 1975).These two historical references give an excellent account of the experimental pathology of inflammation and highlight aspects that are generally ignored in more recent texts that focus on molecular events.

    Google Scholar 

  3. Jay, S. J., Johanson, W. G. Jr & Pierce, A. K. The radiographic resolution of Streptococcus pneumoniae pneumonia. N. Engl. J. Med. 293, 798–801 (1975).

    Article  CAS  Google Scholar 

  4. Deepe, G. S. Jr & Eagleton, L. E. Resolution of influenzal pneumonia. IMJ Ill. Med. J. 158, 76–78 (1980).

    PubMed  Google Scholar 

  5. Metlay, J. P., Atlas, S. J., Borowsky, L. H. & Singer, D. E. Time course of symptom resolution in patients with community-acquired pneumonia. Respir. Med. 92, 1137–1142 (1998).

    Article  CAS  Google Scholar 

  6. Larsen, G. L. & Henson, P. M. Mediators of inflammation. Annu. Rev. Immunol. 1, 335–359 (1983).

    Article  CAS  Google Scholar 

  7. Shanley, T. P., Warner, R. L. & Ward, P. A. The role of cytokines and adhesion molecules in the development of inflammatory injury. Mol. Med. Today 1, 40–45 (1995).

    Article  CAS  Google Scholar 

  8. Spector, W. G. & Willoughby, D. A. Local treatment of experimental burns with a monoamine oxidase inhibitor. Nature 189, 489–490 (1961).

    Article  Google Scholar 

  9. Spector, W. G., Walters, M. & Willoughby, D. A. Venular and capillary permeability in thermal injury. J. Path. Bacteriol. 90, 635–640 (1965).

    Article  CAS  Google Scholar 

  10. Spector, W. G. & Willoughby, D. A. Suppression of increased capillary permeability in injury by monoamine oxidase inhibitors. Nature 186, 162–163 (1960).

    Article  CAS  Google Scholar 

  11. Ottonello, L., Morone, M. P., Dapino, P. & Dallegri, F. Cyclic AMP-elevating agents down-regulate the oxidative burst induced by granulocyte–macrophage colony-stimulating factor (GM-CSF) in adherent neutrophils. Clin. Exp. Immunol. 101, 502–506 (1995).

    Article  CAS  Google Scholar 

  12. Moore, A. R. & Willoughby, D. A. The role of cAMP regulation in controlling inflammation. Clin. Exp. Immunol. 101, 387–389 (1995).

    Article  CAS  Google Scholar 

  13. Adcock, I. M. Molecular mechanisms of glucocorticoids actions. Pulm. Pharmacol. Ther. 13, 115–126 (2000).

    Article  CAS  Google Scholar 

  14. Goulding, N. J. et al. Anti-inflammatory lipocortin 1 production by peripheral-blood leucocytes in response to hydrocortisone. Lancet 335, 1416–1418 (1990).

    Article  CAS  Google Scholar 

  15. Cirino, G. & Flower, R. J. Human recombinant lipocortin 1 inhibits prostacyclin production by human umbilical artery in vitro. Prostaglandins 34, 59–62 (1987).

    Article  CAS  Google Scholar 

  16. Perretti, M. & Flower, R. J. Modulation of IL-1-induced neutrophil migration by dexamethasone and lipocortin 1. J. Immunol. 150, 992–999 (1993).

    CAS  PubMed  Google Scholar 

  17. Serhan, C. N. Lipoxin biosynthesis and its impact in inflammatory and vascular events. Biochim. Biophys. Acta 1212, 1–25 (1994).

    Article  CAS  Google Scholar 

  18. Soyombo, O., Spur, B. W. & Lee, T. H. Effects of lipoxin A4 on chemotaxis and degranulation of human eosinophils stimulated by platelet-activating factor and N-formyl-l- methionyl-l-leucyl-l-phenylalanine. Allergy 49, 230–234 (1994).

    Article  CAS  Google Scholar 

  19. Maddox, J. F. et al. Lipoxin B4 regulates human monocyte/neutrophil adherence and motility: design of stable lipoxin B4 analogs with increased biologic activity. FASEB J. 12, 487–494 (1998).

    Article  CAS  Google Scholar 

  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).

    Article  CAS  Google Scholar 

  21. Raud, J., Palmertz, U., Dahlen, S. E. & Hedqvist, P. Lipoxins inhibit microvascular inflammatory actions of leukotriene B4. Adv. Exp. Med. Biol. 314, 185–192 (1991).

    Article  CAS  Google Scholar 

  22. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  24. Gilroy, D. W. et al. Inducible cyclooxygenase may have anti-inflammatory properties. Nature Med. 5, 698–701 (1999).This paper presents experimental evidence that 15deoxyΔ12,14PGJ 2 is an endogenous anti-inflammatory mediator in vivo.

    Article  CAS  Google Scholar 

  25. Bandeira-Melo, C. et al. Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic oedema in Angiostrongylus costaricensis-infected rats: relationship with concurrent eosinophilia. J. Immunol. 164, 1029–1036 (2000).

    Article  CAS  Google Scholar 

  26. Ianaro, A., Ialenti, A., Maffia, P., Pisano, B. & Di Rosa, M. Role of cyclopentenone prostaglandins in rat carrageenin pleurisy. FEBS Lett. 508, 61–66 (2001).

    Article  CAS  Google Scholar 

  27. 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).

    Article  CAS  Google Scholar 

  28. Kawahito, Y. et al. 15-deoxy-Δ12,14-PGJ2 induces synoviocyte apoptosis and suppresses adjuvant-induced arthritis in rats. J. Clin. Invest. 106, 189–197 (2000).

    Article  CAS  Google Scholar 

  29. Diab, A. et al. Peroxisome proliferator-activated receptor-γ agonist 15-deoxy-Δ12,14-prostaglandin J2 ameliorates experimental autoimmune encephalomyelitis. J. Immunol. 168, 2508–2515 (2002).

    Article  CAS  Google Scholar 

  30. Clark, R. B. et al. The nuclear receptor PPARγ and immunoregulation: PPARγ mediates inhibition of helper T-cell responses. J. Immunol. 164, 1364–1371 (2000).

    Article  CAS  Google Scholar 

  31. Reilly, C. M. et al. Inhibition of mesangial-cell nitric oxide in MRL/lpr mice by prostaglandin J2 and proliferator activation receptor-γ agonists. J. Immunol. 164, 1498–1504 (2000).

    Article  CAS  Google Scholar 

  32. Combs, C. K., Johnson, D. E., Karlo, J. C., Cannady, S. B. & Landreth, G. E. Inflammatory mechanisms in Alzheimer's disease: inhibition of β-amyloid-stimulated proinflammatory responses and neurotoxicity by PPARγ agonists. J. Neurosci. 20, 558–567 (2000).

    Article  CAS  Google Scholar 

  33. Pasceri, V., Wu, H. D., Willerson, J. T. & Yeh, E. T. Modulation of vascular inflammation in vitro and in vivo by peroxisome proliferator-activated receptor-γ activators. Circulation 101, 235–238 (2000).

    Article  CAS  Google Scholar 

  34. Jackson, S. M. et al. Peroxisome proliferator-activated receptor activators target human endothelial cells to inhibit leucocyte–endothelial-cell interaction. Arterioscler. Thromb. Vasc. Biol. 19, 2094–2104 (1999).

    Article  CAS  Google Scholar 

  35. Vaidya, S., Somers, E. P., Wright, S. D., Detmers, P. A. & Bansal, V. S. 15-deoxy-Δ12,1412,14-prostaglandin J2 inhibits the β2 integrin-dependent oxidative burst: involvement of a mechanism distinct from peroxisome proliferator-activated receptor-γ ligation. J. Immunol. 163, 6187–6192 (1999).

    CAS  PubMed  Google Scholar 

  36. Zhang, X., Wang, J. M., Gong, W. H., Mukaida, N. & Young, H. A. Differential regulation of chemokine gene expression by 15-deoxy-Δ12,14 prostaglandin J2 . J. Immunol. 166, 7104–7111 (2001).

    Article  CAS  Google Scholar 

  37. Rossi, A., Elia, G. & Santoro, M. G. Inhibition of nuclear factor κB by prostaglandin A1: an effect associated with heat shock transcription factor activation. Proc. Natl. Acad. Sci. USA 94, 746–750 (1997).

    Article  CAS  Google Scholar 

  38. Ricote, M., Li, A. C., Willson, T. M., Kelly, C. J. & Glass, C. K. The peroxisome proliferator-activated receptor-γ is a negative regulator of macrophage activation. Nature 391, 79–82 (1998).

    Article  CAS  Google Scholar 

  39. Jiang, C., Ting, A. T. & Seed, B. PPAR-γ agonists inhibit production of monocyte inflammatory cytokines. Nature 391, 82–86 (1998).References 38 and 39 were published simultaneously in Nature and identify 15deoxyΔ12,14PGJ 2 as a potent modulator of macrophage activation in vitro.

    Article  CAS  Google Scholar 

  40. Colville-Nash, P. R., Qureshi, S. S., Willis, D. & Willoughby, D. A. Inhibition of inducible nitric oxide synthase by peroxisome proliferator-activated receptor agonists: correlation with induction of heme oxygenase 1. J. Immunol. 161, 978–984 (1998).

    CAS  PubMed  Google Scholar 

  41. Castrillo, A., Diaz-Guerra, M. J., Hortelano, S., Martin-Sanz, P. & Bosca, L. Inhibition of IκB kinase and IκB phosphorylation by 15-deoxy-Δ12,14-prostaglandin J2 in activated murine macrophages. Mol. Cell. Biol. 20, 1692–1698 (2000).

    Article  CAS  Google Scholar 

  42. Straus, D. S. et al. 15-deoxy-Δ12,14-prostaglandin J2 inhibits multiple steps in the NF-κB signaling pathway. Proc. Natl Acad. Sci. USA 97, 4844–4849 (2000).

    Article  CAS  Google Scholar 

  43. Haslett, C. Granulocyte apoptosis and its role in the resolution and control of lung inflammation. Am. J. Respir. Crit. Care Med. 160, S5–S11 (1999).An excellent review of the role of granulocyte apoptosis in the resolution of inflammation.

    Article  CAS  Google Scholar 

  44. Savill, J. & Fadok, V. Corpse clearance defines the meaning of cell death. Nature 407, 784–788 (2000).This review describes how the recognition and phagocytosis of apoptotic cells might regulate the inflammatory response.

    Article  CAS  Google Scholar 

  45. Lawrence, T., Gilroy, D. W., Colville-Nash, P. R. & Willoughby, D. A. Possible new role for NF-κB in the resolution of inflammation. Nature Med. 7, 1291–1297 (2001).

    Article  CAS  Google Scholar 

  46. Bishop-Bailey, D. & Hla, T. Endothelial-cell apoptosis induced by the peroxisome proliferator-activated receptor (PPAR) ligand 15-deoxy-Δ12,14-prostaglandin J2 . J. Biol. Chem. 274, 17042–17048 (1999).

    Article  CAS  Google Scholar 

  47. Khoshnan, A. et al. The NF-κB cascade is important in Bcl-xL expression and for the anti-apoptotic effects of the CD28 receptor in primary human CD4+ lymphocytes. J. Immunol. 165, 1743–1754 (2000).

    Article  CAS  Google Scholar 

  48. 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).

    Article  CAS  Google Scholar 

  49. Fadok, V. A. 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).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  51. van Lent, P. L. et al. Uptake of apoptotic leucocytes by synovial lining macrophages inhibits immune complex-mediated arthritis. J. Leukocyte Biol. 70, 708–714 (2001).

    CAS  PubMed  Google Scholar 

  52. Dibbert, B. et al. Cytokine-mediated Bax deficiency and consequent delayed neutrophil apoptosis: a general mechanism to accumulate effector cells in inflammation. Proc. Natl Acad. Sci. USA 96, 13330–13335 (1999).This paper presents evidence for defects in apoptosis in clinical samples from patients with inflammatory lung disease.

    Article  CAS  Google Scholar 

  53. Vandivier, R. W. et al. Elastase-mediated phosphatidylserine receptor cleavage impairs apoptotic-cell clearance in cystic fibrosis and bronchiectasis. J. Clin. Invest. 109, 661–670 (2002).

    Article  CAS  Google Scholar 

  54. 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).

    Article  CAS  Google Scholar 

  55. Straus, D. S. & Glass, C. K. Cyclopentenone prostaglandins: new insights on biological activities and cellular targets. Med. Res. Rev. 21, 185–210 (2001).

    Article  CAS  Google Scholar 

  56. Clark, R. B. The role of PPARs in inflammation and immunity. J. Leukocyte Biol. 71, 388–400 (2002).

    CAS  PubMed  Google Scholar 

  57. Rossi, A. et al. Anti-inflammatory cyclopentenone prostaglandins are direct inhibitors of IκB kinase. Nature 403, 103–108 (2000).This study identified IKKβ as a specific target of 15deoxyΔ12,14PGJ 2.

    Article  CAS  Google Scholar 

  58. Cernuda-Morollon, E., Pineda-Molina, E., Canada, F. J. & Perez-Sala, D. 15-deoxy-Δ12,14-prostaglandin J2 inhibition of NF-κB–DNA binding through covalent modification of the p50 subunit. J. Biol. Chem. 276, 35530–35536 (2001).

    Article  CAS  Google Scholar 

  59. Karin, M. & Ben-Neriah, Y. Phosphorylation meets ubiquitination: the control of NF-κB activity. Annu. Rev. Immunol. 18, 621–663 (2000).

    Article  CAS  Google Scholar 

  60. Ward, C. et al. NF-κB activation is a critical regulator of human granulocyte apoptosis in vitro. J. Biol. Chem. 274, 4309–4318 (1999).

    Article  CAS  Google Scholar 

  61. Fierro, I. M. & Serhan, C. N. Mechanisms in anti-inflammation and resolution: the role of lipoxins and aspirin-triggered lipoxins. Braz. J. Med. Biol. Res. 34, 555–566 (2001).

    Article  CAS  Google Scholar 

  62. Levy, B. D. et al. Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A4 . Nature Med. 8, 1018–1023 (2002).

    Article  CAS  Google Scholar 

  63. Shibata, T. et al. 15-deoxy-Δ12,14-prostaglandin J2. A prostaglandin D2 metabolite generated during inflammatory processes. J. Biol. Chem. 277, 10459–10466 (2002).

    Article  CAS  Google Scholar 

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Acknowledgements

T. L. would like to acknowledge financial support of the Arthritis Research Campaign and The Special Trustees of St Bartholomew's Hospital Joint Research Board. D. W. would like to acknowledge financial support of the William Harvey Research Foundation.

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Correspondence to Toby Lawrence.

Supplementary information

41577_2002_BFnri915_MOESM1_ESM.gif

Online figure 1| Biochemical pathway for arachidonic-acid release and eicosanoid biosynthesis. Arachidonic acid is liberated through the action of phospholipase enzymes, and converted to prostaglandin G2 (PGG2) and, subsequently, PGH2 by cyclooxygenase. Specific synthase enzymes then generate the different classes of prostaglandin. PLA2, phospholipase A2 (c, cytosolic; i, Ca2+ independent; s, secretory); hPGD2S, prostaglandin D2 synthase; mPGE2S/cPGE2S, prostaglandin E2 synthase; TxA2, thromboxane A2. (GIF 39 kb)

41577_2002_BFnri915_MOESM2_ESM.gif

Online figure 2| Biochemical pathway for lipoxin biosynthesis. The sequential action of 12- or 15-lipoxygenase (LO) and specific lipoxin hydrolase enzymes generates lipoxin A4 (LXA4) and LXB4 from leukotriene A4 (LTA4). (GIF 18 kb)

41577_2002_BFnri915_MOESM3_ESM.gif

Online figure 3| Cyclopentenone-prostaglandin formation. Prostaglandin D2 (PGD2), PGE2 and PGE1 are spontaneously metabolized to the cyclopentenone derivatives PGJ2, PGA2 and PGA1, respectively, by dehydrogenation. These cyclopentenone prostaglandins share the structural feature of a reactive carbonyl group in the cyclopentane ring. (GIF 19 kb)

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DATABASES

OMIM

Alzheimer's disease

asthma

cystic fibrosis

inflammatory bowel disease

multiple sclerosis

psoriasis

rheumatoid arthritis

SLE

LocusLink

annexin 1

β-amyloid

BCL-XL

CCL11

CD28

COX2

E-selectin

ICAM1

IκBα

IKKα

IKKβ

IL-1β

IL-2

IL-6

IL-8

iNOS

MCP1

myelin basic protein

NF-κB1

PECAM1

PPARγ

RELA

TGF-β1

TNF

VCAM1

Glossary

STOP SIGNALS

This term was coined to introduce the concept of a cellular agonist that acts as an inhibitor of inflammation.

CYCLOPENTENONE PROSTAGLANDINS

Prostaglandin metabolites that are characterized by the presence of a highly reactive electrophilic carbon atom in the unsaturated carbonyl group of the cyclopentane ring.

LIPOXINS

Leukocyte-derived eicosanoids generated during the inflammatory response that act as downregulatory signals.

EICOSANOIDS

A class of lipid mediator that have twenty-carbon fatty-acid derivatives; from the Greek eicosa, meaning 20. Eicosanoids are fatty-acid derivatives, primarily derived from arachidonic-acid precursors, that have a wide variety of biological activities. There are four main classes of eicosanoid — the prostaglandins, prostacyclins, thromboxanes and leukotrienes — derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty-acid precursors.

LIPOXYGENASE

A nonheme iron dioxygenase that is the key enzyme in leukotriene production.

TRANSCELLULAR BIOSYNTHESIS

A biosynthetic pathway that is dependent on molecules transferred from one cell to another.

CYCLOOXYGENASE 2

(COX2). An inducible cyclooxygenase enzyme that is thought to be the main producer of prostaglandins during the inflammatory response.

TRANSACTIVATION

The activation of gene transcription by trans-acting factors, such as protein transcription factors, as opposed to cis-acting DNA elements, such as enhancers/promoters.

CYCLOOXYGENASE PATHWAY

A biochemical pathway for the intracellular production of prostaglandins from arachidonic acid.

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Lawrence, T., Willoughby, D. & Gilroy, D. Anti-inflammatory lipid mediators and insights into the resolution of inflammation. Nat Rev Immunol 2, 787–795 (2002). https://doi.org/10.1038/nri915

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