Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Pro-resolving lipid mediators are leads for resolution physiology

Subjects

Abstract

Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.

This is a preview of subscription content, access via your institution

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: Lipid mediators in the acute inflammatory response, resolution and other outcomes.
Figure 2: Production of specialized pro-resolving mediators in resolving inflammatory exudates.

References

  1. Flower, R. J. Prostaglandins, bioassay and inflammation. Br. J. Pharmacol. 147, S182–S192 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Samuelsson, B. Role of basic science in the development of new medicines: examples from the eicosanoid field. J. Biol. Chem. 287, 10070–10080 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Dinarello, C. A., Simon, A. & van der Meer, J. W. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nature Rev. Drug Discov. 11, 633–652 (2012).

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  5. Maderna, P. & Godson, C. Lipoxins: resolutionary road. Br. J. Pharmacol. 158, 947–959 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tabas, I. & Glass, C. K. Anti-inflammatory therapy in chronic disease: challenges and opportunities. Science 339, 166–172 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  7. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Lands, W. E. M. Fish, Omega-3 and Human Health 2nd edn (AOCS Press, 2005).

    Book  Google Scholar 

  10. Serhan, C. N. & Chiang, N. Resolution phase lipid mediators of inflammation: agonists of resolution. Curr. Opin. Pharmacol. 13, 632–640 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Malawista, S. E., de Boisfleury Chevance, A., van Damme, J. & Serhan, C. N. Tonic inhibition of chemotaxis in human plasma. Proc. Natl Acad. Sci. USA 105, 17949–17954 (2008).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  12. Fullerton, J. N., O'Brien, A. J. & Gilroy, D. W. Lipid mediators in immune dysfunction after severe inflammation. Trends Immunol. 35, 12–21 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Dalli, J. & Serhan, C. N. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood 120, e60–e72 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Serhan, C. N. The resolution of inflammation: the devil in the flask and in the details. FASEB J. 25, 1441–1448 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Bailey, R. L., Gahche, J. J., Miller, P. E., Thomas, P. R. & Dwyer, J. T. Why US adults use dietary supplements. JAMA Intern. Med. 173, 355–361 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Yates, C. M., Calder, P. C. & Rainger, G. E. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. Pharmacol. Ther. 141, 272–282 (2014). A thoughtful review of the use of omega-3 essential fatty acids in inflammatory diseases and their potential in supplementation, dietary manipulation and pharmacology.

    Article  CAS  PubMed  Google Scholar 

  17. Serhan, C. N. & Petasis, N. A. Resolvins and protectins in inflammation-resolution. Chem. Rev. 111, 5922–5943 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Schwab, J. M., Chiang, N., Arita, M. & Serhan, C. N. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature 447, 869–874 (2007).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  19. Miyahara, T. et al. D-series resolvins attenuate vascular smooth muscle cell activation and neointimal hyperplasia following vascular injury. FASEB J. 27, 2220–2232 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Levy, B. D. & Serhan, C. N. Resolution of acute inflammation in the lung. Annu. Rev. Physiol. 76, 467–492 (2014).

    Article  CAS  PubMed  Google Scholar 

  21. Spite, M., Claria, J. & Serhan, C. N. Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab. 19, 21–36 (2014).

    Article  CAS  PubMed  Google Scholar 

  22. Dalli, J. et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem. Biol. 20, 188–201 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Serhan, C. N. et al. Macrophage pro-resolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. 26, 1755–1765 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dalli, J. et al. The novel 13S,14S-epoxy-maresin is converted by human macrophages to maresin1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 27, 2573–2583 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Biswas, S. K. & Mantovani, A. Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunol. 11, 889–896 (2010).

    Article  CAS  Google Scholar 

  26. 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 

  27. Morris, T. et al. Effects of low-dose aspirin on acute inflammatory responses in humans. J. Immunol. 183, 2089–2096 (2009).

    Article  CAS  PubMed  Google Scholar 

  28. 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  PubMed  PubMed Central  Google Scholar 

  29. Chan, M. M.-Y. & Moore, A. R. Resolution of inflammation in murine autoimmune arthritis is disrupted by cyclooxygenase-2 inhibition and restored by prostaglandin E2-mediated lipoxin A4 production. J. Immunol. 184, 6418–6426 (2010).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  31. Lucas, C. D. et al. Downregulation of Mcl-1 has anti-inflammatory pro-resolution effects and enhances bacterial clearance from the lung. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2013.102 (2013).

  32. Navarro-Xavier, R. A. et al. A new strategy for the identification of novel molecules with targeted proresolution of inflammation properties. J. Immunol. 184, 1516–1525 (2010).

    Article  CAS  PubMed  Google Scholar 

  33. Chiang, N. et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524–528 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  34. Spite, M. et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature 461, 1287–1291 (2009).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  35. Birnbaum, Y. et al. Augmentation of myocardial production of 15-epi-lipoxin-A4 by pioglitazone and atorvastatin in the rat. Circulation 114, 929–935 (2006). This is the first description of 15-epi-LXA 4 biosynthesis by statins in vivo in rats using a novel pathway and phosphorylated enzymes in the biosynthesis of 15-epi-LXA 4 that mimic the biosynthetic capacity of acetylated COX-2.

    Article  CAS  PubMed  Google Scholar 

  36. Cooray, S. N. et al. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc. Natl Acad. Sci. USA 110, 18232–18237 (2013). This article reports exciting results indicating that heterodimers and homodimers of ALX/FPR2 signal different responses by activation of distinct intracellular signalling mechanisms.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  37. Serhan, C. N. et al. Novel proresolving aspirin-triggered DHA pathway. Chem. Biol. 18, 976–987 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Morris, T. et al. Dichotomy in duration and severity of acute inflammatory responses in humans arising from differentially expressed proresolution pathways. Proc. Natl Acad. Sci. USA 107, 8842–8847 (2010).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  39. Brancaleone, V. et al. A vasculo-protective circuit centered on lipoxin A4 and aspirin-triggered 15-epi-lipoxin A4 operative in murine microcirculation. Blood 122, 608–617 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Norling, L. V. et al. Cutting edge: humanized nano-proresolving medicines mimic inflammation-resolution and enhance wound healing. J. Immunol. 186, 5543–5547 (2011).

    Article  CAS  PubMed  Google Scholar 

  41. Stables, M. J. et al. Transcriptomic analyses of murine resolution-phase macrophages. Blood 118, e192–e208 (2011).

    Article  CAS  PubMed  Google Scholar 

  42. Miki, Y. et al. Lymphoid tissue phospholipase A2 group IID resolves contact hypersensitivity by driving antiinflammatory lipid mediators. J. Exp. Med. 210, 1217–1234 (2013). This article reports the identification of a secretory phospholipase A2 activated during contact hypersensitive reactions that is specifically involved in the generation of resolvin D1 and protectin D1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Levy, B. D. et al. Protectin D1 is generated in asthma and dampens airway inflammation and hyper-responsiveness. J. Immunol. 178, 496–502 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Miyata, J. et al. Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma. J. Allergy Clin. Immunol. 131, 353–360 (2013).

    Article  CAS  PubMed  Google Scholar 

  45. Yamada, T. et al. Eosinophils promote resolution of acute periotonitis by producing proresolving mediators in mice. FASEB J. 25, 561–568 (2011).

    Article  CAS  PubMed  Google Scholar 

  46. Isobe, Y. et al. Stereochemical assignment and anti-inflammatory properties of the omega-3 lipid mediator resolvin E3. J. Biochem. 153, 355–360 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Ohira, T. et al. Resolvin E1 receptor activation signals phosphorylation and phagocytosis. J. Biol. Chem. 285, 3451–3461 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. El Kebir, D., Gjorstrup, P. & Filep, J. G. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc. Natl Acad. Sci. USA 109, 14983–14988 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  50. Krishnamoorthy, S., Recchiuti, A., Chiang, N., Fredman, G. & Serhan, C. N. Resolvin D1 receptor stereoselectivity and regulation of inflammation and pro-resolving microRNAs. Am. J. Pathol. 180, 2018–2027 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Norling, L. V., Dalli, J., Flower, R. J., Serhan, C. N. & Perretti, M. Resolvin D1 limits polymorphonuclear leukocytes recruitment to inflammatory loci: receptor dependent actions. Arterioscler. Thromb. Vasc. Biol. 32, 1970–1978 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Fredman, G., Li, Y., Dalli, J., Chiang, N. & Serhan, C. N. Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA. Sci. Rep. 2, 639 (2012).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  53. Li, Y. et al. Plasticity of leukocytic exudates in resolving acute inflammation is regulated by microRNA and proresolving mediators. Immunity 39, 885–898 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Li, D. et al. Resolvin D1 and aspirin-triggered resolvin D1 regulate histamine-stimulated conjunctival goblet cell secretion. Mucosal Immunol. http://dx.doi.org/10.1038/mi.2013.7 (2013).

  55. Nelson, J. et al. The ALX/FPR2 receptor for RvD1 is expressed and functional in salivary glands. Am. J. Physiol. Cell Physiol. 306, C178–C185 (2014).

    Article  ADS  CAS  PubMed  Google Scholar 

  56. Jones, C. N. et al. Microfluidic chambers for monitoring leukocyte trafficking and humanized nano-proresolving medicines interactions. Proc. Natl Acad. Sci. USA 109, 20560–20565 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kasuga, K. et al. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. J. Immunol. 181, 8677–8687 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Simiele, F. et al. Transcriptional regulation of the human FPR2/ALX gene: evidence of a heritable genetic variant that impairs promoter activity. FASEB J. 26, 1323–1333 (2012).

    Article  CAS  PubMed  Google Scholar 

  59. Serhan, C. N. et al. Reduced inflammation and tissue damage in transgenic rabbits overexpressing 15-lipoxygenase and endogenous anti-inflammatory lipid mediators. J. Immunol. 171, 6856–6865 (2003).

    Article  CAS  PubMed  Google Scholar 

  60. Hasturk, H. et al. Resolvin E1 regulates inflammation at the cellular and tissue level and restores tissue homeostasis in vivo. J. Immunol. 179, 7021–7029 (2007).

    Article  CAS  PubMed  Google Scholar 

  61. Oh, S. F., Pillai, P. S., Recchiuti, A., Yang, R. & Serhan, C. N. Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J. Clin. Invest. 121, 569–581 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Walker, J. et al. Lipoxin A4 increases survival by decreasing systemic inflammation and bacterial load in sepsis. Shock 36, 410–416 (2011).

    Article  CAS  PubMed  Google Scholar 

  63. Prescott, D. & McKay, D. M. Aspirin-triggered lipoxin enhances macrophage phagocytosis of bacteria while inhibiting inflammatory cytokine production. Am. J. Physiol. Gastrointest. Liver Physiol. 301, G487–G497 (2011).

    Article  CAS  PubMed  Google Scholar 

  64. Divangahi, M. et al. Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair. Nature Immunol. 10, 899–906 (2009).

    Article  CAS  Google Scholar 

  65. Tobin, D. M. et al. Host genotype-specific therapies can optimize the inflammatory response to mycobacterial infections. Cell 148, 434–446 (2012). This systematic analysis of tuberculosis in infections in zebrafish identified the host gradation response to producing excess LTB 4 or excess LXA 4 , each having different outcomes for the host and the clearance of tuberculosis infections.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Rajasagi, N. K., Reddy, P. B., Mulik, S., Gjorstrup, P. & Rouse, B. T. Neuroprotectin D1 reduces the severity of herpes simplex virus-induced corneal immunopathology. Invest. Ophthalmol. Vis. Sci. 54, 6269–6279 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rajasagi, N. K. et al. Controlling herpes simplex virus-induced ocular inflammatory lesions with the lipid-derived mediator resolvin E1. J. Immunol. 186, 1735–1746 (2011). This is an exciting first report demonstrating that resolvin E1 protects the eye from Herpes simplex virus infection and stimulates clearance of the virus.

    Article  CAS  PubMed  Google Scholar 

  68. Cilloniz, C. et al. Lethal dissemination of H5N1 influenza virus is associated with dysregulation of inflammation and lipoxin signaling in a mouse model of infection. J. Virol. 84, 7613–7624 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Morita, M. et al. The lipid mediator protectin D1 inhibits influenza virus replication and improves severe influenza. Cell 153, 112–125 (2013).

    Article  CAS  PubMed  Google Scholar 

  70. Tam, V. C. et al. Lipidomic profiling of influenza infection identifies mediators that induce and resolve inflammation. Cell 154, 213–227 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Haas-Stapleton, E. J. et al. Candida albicans modulates host defense by biosynthesizing the pro-resolving mediator resolvin E1. PLoS ONE 2, e1316 (2007).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  72. Baillie, J. K. & Digard, P. Influenza–time to target the host? N. Engl. J. Med. 369, 191–193 (2013).

    Article  CAS  PubMed  Google Scholar 

  73. Pouliot, M., Clish, C. B., Petasis, N. A., Van Dyke, T. E. & Serhan, C. N. Lipoxin A4 analogues inhibit leukocyte recruitment to Porphyromonas gingivalis: a role for cyclooxygenase-2 and lipoxins in periodontal disease. Biochemistry 39, 4761–4768 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Shen, J. et al. Macrophage-mediated 15-lipoxygenase expression protects against atherosclerosis development. J. Clin. Invest. 98, 2201–2208 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Merched, A. J., Ko, K., Gotlinger, K. H., Serhan, C. N. & Chan, L. Atherosclerosis: evidence for impairment of resolution of vascular inflammation governed by specific lipid mediators. FASEB J. 22, 3595–3606 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Merched, A. J., Serhan, C. N. & Chan, L. Nutrigenetic disruption of inflammation-resolution homeostasis and atherogenesis. J. Nutrigenet. Nutrigenomics 4, 12–24 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Hasturk, H. et al. RvE1 protects from local inflammation and osteoclast mediated bone destruction in periodontitis. FASEB J. 20, 401–403 (2006).

    Article  CAS  PubMed  Google Scholar 

  78. Lima-Garcia, J. F. et al. The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br. J. Pharmacol. 164, 278–293 (2011). The authors of this article demonstrate that 17-HDHA and aspirin-triggered RvD1 have potent protective actions in adjuvant-induced arthritis and reduce pain in this model of arthritis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Kowal-Bielecka, O., Kowal, K., Distler, O. & Gay, S. Mechanisms of disease: leukotrienes and lipoxins in scleroderma lung disease–insights and potential therapeutic implications. Nature Clin. Pract. Rheumatol. 3, 43–51 (2007).

    Article  CAS  Google Scholar 

  80. Martins, V. et al. ATLa, an aspirin-triggered lipoxin A4 synthetic analog, prevents the inflammatory and fibrotic effects of bleomycin-induced pulmonary fibrosis. J. Immunol. 182, 5374–5381 (2009).

    Article  CAS  PubMed  Google Scholar 

  81. Börgeson, E. et al. Lipoxin A(4) and benzo-lipoxin A(4) attenuate experimental renal fibrosis. FASEB J. 25, 2967–2979 (2011). This article reported that expediting resolution and counter-regulation of pro-inflammatory mediators by administration of LXA 4 or its analogues can prevent organ fibrosis and renal fibrosis.

    Article  PubMed  CAS  Google Scholar 

  82. Qu, X. et al. Resolvins E1 and D1 inhibit interstitial fibrosis in the obstructed kidney via inhibition of local fibroblast proliferation. J. Pathol. 228, 506–519 (2012).

    Article  CAS  PubMed  Google Scholar 

  83. Hsiao, H. M. et al. A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. PLoS ONE 8, e58258 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang, S. B. et al. Estrogen negatively regulates epithelial wound healing and protective lipid mediator circuits in the cornea. FASEB J. 26, 1506–1516 (2012).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  85. Menon, R. The Effect of Resolvins on Dermal Wound Healing. MS thesis, Rutgers Univ. (2012).

    Google Scholar 

  86. Tang, Y. et al. Proresolution therapy for the treatment of delayed healing of diabetic wounds. Diabetes 62, 618–627 (2013). In this article, the authors demonstrate that pro-resolving mediators such as RvD1 can expedite healing of wounds encountered in diabetes.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Ramon, S., Gao, F., Serhan, C. N. & Phipps, R. P. Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. J. Immunol. 189, 1036–1042 (2012).

    Article  CAS  PubMed  Google Scholar 

  88. Hong, S. et al. Resolvin D1, protectin D1, and related docosahexaenoic acid-derived products: analysis via electrospray/low energy tandem mass spectrometry based on spectra and fragmentation mechanisms. J. Am. Soc. Mass Spectrom. 18, 128–144 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Ariel, A. et al. The docosatriene protectin D1 is produced by TH2 skewing and promotes human T cell apoptosis via lipid raft clustering. J. Biol. Chem. 280, 43079–43086 (2005).

    Article  CAS  PubMed  Google Scholar 

  90. Ariel, A. et al. Apoptotic neutrophils and T cells sequester chemokines during immune response resolution via modulation of CCR5 expression. Nature Immunol. 7, 1209–1216 (2006).

    Article  CAS  Google Scholar 

  91. Settimio, R., Clara, D. F., Franca, F., Francesca, S. & Michele, D. Resolvin D1 reduces the immunoinflammatory response of the rat eye following uveitis. Mediators Inflamm. 2012, 318621 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Tian, H., Lu, Y., Sherwood, A. M., Hongqian, D. & Hong, S. Resolvins E1 and D1 in choroid-retinal endothelial cells and leukocytes: biosynthesis and mechanisms of anti-inflammatory actions. Invest. Ophthalmol. Vis. Sci. 50, 3613–3620 (2009). The authors of this report demonstrate the endogenous biosynthesis of RvE1 and RvD1 in the retina and the role of cell–cell interactions in this organ.

    Article  PubMed  Google Scholar 

  93. Vassiliou, E. K., Kesler, O. M., Tadros, J. H. & Ganea, D. Bone marrow-derived dendritic cells generated in the presence of resolvin E1 induce apoptosis of activated CD4+ T cells. J. Immunol. 181, 4534–4544 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Kim, T. H., Kim, G. D., Jin, Y. H., Park, Y. S. & Park, C. S. Omega-3 fatty acid-derived mediator, Resolvin E1, ameliorates 2,4-dinitrofluorobenzene-induced atopic dermatitis in NC/Nga mice. Int. Immunopharmacol. 14, 384–391 (2012).

    Article  CAS  PubMed  Google Scholar 

  95. 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).

    Article  CAS  PubMed  Google Scholar 

  96. Lukiw, W. J. et al. A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774–2783 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. 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). This is an important first report of the production and actions of NPD1 in the mouse brain and its neural function by reducing inflammation.

    Article  CAS  PubMed  Google Scholar 

  98. Bazan, N. G., Calandria, J. M. & Serhan, C. N. Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1. J. Lipid Res. 51, 2018–2031 (2010). An authoritative, critical review of the bioactivity and actions of NPD1 in the eye and brain.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Sheets, K. G. et al. Microglial ramification and redistribution concomitant with the attenuation of choroidal neovascularization by neuroprotectin D1. Mol. Vis. 19, 1747–1759 (2013). The article is the first description of NPD1 action in regulating neovascularization by targeting microglia.

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Bazan, N. G. et al. Novel aspirin-triggered neuroprotectin D1 attenuates cerebral ischemic injury after experimental stroke. Exp. Neurol. 236, 122–130 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Wang, X. et al. Resolution of inflammation is altered in Alzheimer's disease. Alzheimers Dement. http://dx.doi.org/10.1016/j.jalz.2013.12.024 (2014).

  102. Mizwicki, M. T. et al. 1α,25-Dihydroxyvitamin D3 and resolvin D1 retune the balance between amyloid-β phagocytosis and inflammation in Alzheimer's disease patients. J. Alzheimers Dis. 34, 155–170 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Svensson, C. I., Zattoni, M. & Serhan, C. N. Lipoxins and aspirin-triggered lipoxin stop inflammatory pain processing. J. Exp. Med. 204, 245–252 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Piomelli, D. & Sasso, O. Peripheral gating of pain signals by endogenous lipid mediators. Nature Neurosci. 17, 164–174 (2014).

    Article  CAS  PubMed  Google Scholar 

  105. Xu, Z.-Z. et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. Nature Med. 16, 592–597 (2010).

    Article  CAS  PubMed  Google Scholar 

  106. Bang, S., Yoo, S., Yang, T. J., Cho, H. & Hwang, S. W. 17(R)-resolvin D1 specifically inhibits transient receptor potential ion channel vanilloid 3 leading to peripheral antinociception. Br. J. Pharmacol. 165, 683–692 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Park, C. K. et al. Resolving TRPV1 and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. J. Neurosci. 31, 15072–15085 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Abdelmoaty, S. et al. Spinal actions of lipoxin A4 and 17(R)-resolvin D1 attenuate inflammation-induced mechanical hypersensitivity and spinal TNF release. PLoS ONE 8, e75543 (2013).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  109. Terrando, N. et al. Aspirin-triggered resolvin D1 prevents surgery-induced cognitive decline. FASEB J. 27, 3564–3571 (2013). This article reports an exciting discovery demonstrating that RvD1 counter-regulates pro-inflammatory mediators produced during surgery-induced cognitive decline.

    Article  CAS  PubMed  Google Scholar 

  110. Psychogios, N. et al. The human serum metabolome. PLoS ONE 6, e16957 (2011).

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  111. Mas, E., Croft, K. D., Zahra, P., Barden, A. & Mori, T. A. Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin. Chem. 58, 1476–1484 (2012).

    Article  CAS  PubMed  Google Scholar 

  112. 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).

    Article  CAS  PubMed  Google Scholar 

  113. Jones, M. L. et al. Maternal dietary omega-3 fatty acid intake increases resolvin and protectin levels in the rat placenta. J. Lipid Res. 54, 2247–2254 (2013). This article is an important contribution demonstrating that resolvins and protectins are present in placenta and that their levels can be substantially increased with dietary supplementation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Weiss, G. A. et al. High levels of anti-inflammatory and pro-resolving lipid mediators lipoxins and resolvins and declining docosahexaenoic acid levels in human milk during the first month of lactation. Lipids Health Dis. 12, 89 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Markworth, J. F. et al. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 305, R1281–R1296 (2013). This article reports exciting new results indicating that strenuous exercise activates acute inflammation and pro-inflammatory eicosanoids, which then transition in humans to pro-resolving mediators present in peripheral blood following a time course consistent with lipid-mediator class switching and resolution of exercise-induced muscle stress or inflammation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Wu, S. H., Chen, X. Q., Liu, B., Wu, H. J. & Dong, L. Efficacy and safety of 15(R/S)-methyl-lipoxin A4 in topical treatment of infantile eczema. Br. J. Dermatol. 168, 172–178 (2013). This article reports a paediatric clinical trial that was the first to demonstrate that the topical addition of an aspirin-triggered LXA 4 stable analogue is safe and effective in reducing infantile eczema.

    Article  CAS  PubMed  Google Scholar 

  117. Raatz, S. K. et al. Baking reduces prostaglandin, resolvin, and hydroxy-fatty acid content of farm-raised Atlantic salmon (Salmo salar). J. Agric. Food Chem. 59, 11278–11286 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Clària, J., Nguyen, B. T., Madenci, A., Ozaki, C. K. & Serhan, C. N. Diversity of lipid mediators in human adipose tissue depots. Am. J. Physiol. Cell Physiol. 304, C1141–C1149 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Prüss, H. et al. Proresolution lipid mediators in multiple sclerosis - differential, disease severity-dependent synthesis — a clinical pilot trial. PLoS ONE 8, e55859 (2013).

    Article  ADS  PubMed  PubMed Central  CAS  Google Scholar 

  120. Giera, M. et al. Lipid and lipid mediator profiling of human synovial fluid in rheumatoid arthritis patients by means of LC-MS/MS. Biochim. Biophys. Acta 1821, 1415–1424 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Colas, R., Shinohara, M., Dalli, J., Chiang, N. & Serhan, C.N. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am. J. Physiol Cell Physiol. http://dx.doi.org/10.1152/ajpcell.00024.2014 (2 April, 2014).

Download references

Acknowledgements

The author thanks S. Orr, J. Dalli and N. Chiang for their critical reading of this manuscript and grants from the US National Institutes of Health (R01GM038765 and P01GM095467) and the Mérieux Foundation (France) for support of the author's research. I also thank our collaborators and investigators contributing to this area whose publications were not cited due to size limitations.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Charles N. Serhan.

Ethics declarations

Competing interests

C.N.S. is an inventor of patents (resolvins) assigned to BWH and licensed to Resolvyx Pharmaceuticals. C.N.S. is a scientific founder of Resolvyx Pharmaceuticals and owns equity in the company. The interests of C.N.S. were reviewed and are managed by the Brigham and Women's Hospital and Partners HealthCare in accordance with their conflict of interest policies.

Additional information

Reprints and permissions information is available at www.nature.com/reprints.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Serhan, C. Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92–101 (2014). https://doi.org/10.1038/nature13479

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature13479

This article is cited by

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.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing