Resolvins in inflammation: Emergence of the pro-resolving superfamily of mediators

Journal of Clinical Investigation

Volumn 128, Issue 7, 2018, Pages 2657-2669

  Serhan, Charles N ^a   Levy, Bruce D ^b  

^a Perioperative and Pain Medicine ^*  (United States)

^b BRIGHAM AND WOMEN S HOSPITAL   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

BIOLOGICAL MARKER; CD59 ANTIGEN; LIPOXIN; MARESIN; RESOLVIN; UNCLASSIFIED DRUG; AUTACOID; DOCOSAHEXAENOIC ACID; UNSATURATED FATTY ACID;

ADAPTIVE IMMUNITY; AGING; ARTHRITIS; BIOMIMETICS; CELL DEATH; HUMAN; IMMUNE RESPONSE; INFLAMMATION; INNATE IMMUNITY; INTRACELLULAR SIGNALING; METABOLOME; NERVOUS SYSTEM; NEUTROPHIL; PHAGOCYTOSIS; PRIORITY JOURNAL; QUANTITATIVE ANALYSIS; REVIEW; TISSUE INJURY; ANIMAL; BIOLOGICAL MODEL; IMMUNOLOGY; IMMUNOMODULATION; METABOLISM; SIGNAL TRANSDUCTION;

ADAPTIVE IMMUNITY; ANIMALS; ARTHRITIS; BIOMARKERS; DOCOSAHEXAENOIC ACIDS; FATTY ACIDS, UNSATURATED; HUMANS; IMMUNITY, INNATE; INFLAMMATION; INFLAMMATION MEDIATORS; LIPOXINS; MODELS, BIOLOGICAL; NEUROIMMUNOMODULATION; NEUTROPHILS; SIGNAL TRANSDUCTION;

EID: 85049846480     PISSN: 00219738     EISSN: 15588238     Source Type: Journal    
DOI: 10.1172/JCI97943     Document Type: Review

References (200)

1. Myers GL, et al. CDC/AHA Workshop on Markers of Inflammation and Cardiovascular Disease: Application to Clinical and Public Health Practice: report from the laboratory science discussion group. Circulation. 2004;110(25):e545–e549.
2. Calder PC. Marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance. Biochim Biophys Acta. 2015;1851(4):469–484.
3. Calder PC. Omega-3 fatty acids and inflammatory processes: from molecules to man. Biochem Soc Trans. 2017;45(5):1105–1115.
4. Cotran RS, Kumar V, Collins T, eds. Robbins Pathologic Basis of Disease. Philadelphia, Pennsylvania, USA: W.B. Saunders Co.; 1999.
5. Malawista SE, de Boisfleury Chevance A, van Damme J, Serhan CN. Tonic inhibition of chemo-taxis in human plasma. Proc Natl Acad Sci U S A. 2008;105(46):17949–17954.
6. Gordon S. Phagocytosis: an immunobiologic process. Immunity. 2016;44(3):463–475.
7. Serhan CN. Pro-resolving lipid mediators are leads for resolution physiology. Nature. 2014;510(7503):92–101.
8. Ward PA. Acute and chronic inflammation. In: Serhan CN, Ward PA, Gilroy DW, eds. Fundamentals of Inflammation. New York, New York, USA: Cambridge University Press; 2010:1–16.
9. Serhan CN, Clish CB, Brannon J, Colgan SP, Chiang N, Gronert K. 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. 2000;192(8):1197–1204.
10. Takano T, Clish CB, Gronert K, Petasis N, Serhan CN. 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. 1998;101(4):819–826.
11. Levy BD, Clish CB, Schmidt B, Gronert K, Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol. 2001;2(7):612–619.
12. Bandeira-Melo C, et al. Cyclooxygenase-2-derived prostaglandin E2 and lipoxin A4 accelerate resolution of allergic edema in Angiostron-gylus costaricensis-infected rats: relationship with concurrent eosinophilia. JImmunol. 2000;164(2):1029–1036.
13. Vane JR, Botting RM, eds. Therapeutic Roles of Selective COX-2 Inhibitors. London, United Kingdom: William Harvey Press; 2001.
14. Dalli J, et al. Resolvin D3 and aspirin-triggered resolvin D3 are potent immunoresolvents. Chem Biol. 2013;20(2):188–201.
15. Serhan CN, Chiang N, Dalli J. New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration [published online ahead of print September 1, 2017]. Mol Aspects Med. https://doi.org/10.1016/j.mam.2017.08.002.
16. Fullerton JN, Gilroy DW. Resolution of inflammation: a new therapeutic frontier. Nat Rev Drug Discov. 2016;15(8):551–567.
17. Perretti M. The resolution of inflammation: new mechanisms in patho-physiology open opportunities for pharmacology. Semin Immunol. 2015;27(3):145–148.
18. Godson C, Mitchell S, Harvey K, Petasis NA, Hogg N, Brady HR. Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages. JImmunol. 2000;164(4):1663–1667.
19. Serhan CN. Lipoxins and novel aspirin-triggered 15-epi-lipoxins (ATL): a jungle of cell-cell interactions or a therapeutic opportunity? Prostaglandins. 1997;53(2):107–137.
20. Serhan CN, et al. Resolution of inflammation: state of the art, definitions and terms. FASEB J. 2007;21(2):325–332.
21. Samuelsson B, Dahlén SE, Lindgren JA, Rouzer CA, Serhan CN. Leukotrienes and lipoxins: structures, biosynthesis, and biological effects. Science. 1987;237(4819):1171–1176.
22. Bannenberg GL, et al. Molecular circuits of resolution: formation and actions of resolvins and protectins. JImmunol. 2005;174(7):4345–4355.
23. Serhan CN, 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. 2002;196(8):1025–1037.
24. Hong S, Gronert K, Devchand PR, Moussignac RL, Serhan CN. Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain, human blood, and glial cells. Autacoids in anti-inflammation. JBiolChem. 2003;278(17):14677–14687.
25. Serhan CN, et al. Maresins: novel macrophage mediators with potent anti-inflammatory and pro-resolving actions. J Exp Med. 2009;206(1):15–23.
26. Dalli J, Chiang N, Serhan CN. Elucidation of novel 13-series resolvins that increase with atorvastatin and clear infections. Nat Med. 2015;21(9):1071–1075.
27. Dalli J, Colas RA, Serhan CN. Novel n-3 immunoresolvents: structures and actions. SciRep. 2013;3:1940.
28. Gilroy DW. The role of aspirin-triggered lipoxins in the mechanism of action of aspirin. Prostaglandins Leukot Essent Fatty Acids. 2005;73(3-4):203–210.
29. Serhan CN. Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J. 2017;31(4):1273–1288.
30. Chiang N, Serhan CN. Structural elucidation and physiologic functions of specialized pro-resolving mediators and their receptors. Mol Aspects Med. 2017;58:114–129.
31. Serhan CN, et al. Novel proresolving aspirin-triggered DHA pathway. Chem Biol. 2011;18(8):976–987.
32. Arita M, et al. Stereochemical assignment, anti-inflammatory properties, and receptor for the omega-3 lipid mediator resolvin E1. JExp Med. 2005;201(5):713–722.
33. Serhan CN, et al. Macrophage proresolving mediator maresin 1 stimulates tissue regeneration and controls pain. FASEB J. 2012;26(4):1755–1765.
34. Serhan CN, et al. Anti-inflammatory actions of neuroprotectin D1/protectin D1 and its natural stereoisomers: assignments of dihy-droxy-containing docosatrienes. J Immunol. 2006;176(3):1848–1859.
35. Sun YP, et al. Resolvin D1 and its aspirin-triggered 17R epimer. Stereochemical assignments, antiinflammatory properties, and enzymatic inactivation. JBiolChem. 2007;282(13):9323–9334.
36. Hansen TV, Dalli J, Serhan CN. The novel lipid mediator PD1n-3 DPA: an overview of the structural elucidation, synthesis, biosynthesis and bioactions. Prostaglandins Other Lipid Mediat. 2017;133:103–110.
37. Chiang N, et al. Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature. 2012;484(7395):524–528.
38. Oh SF, Pillai PS, Recchiuti A, Yang R, Serhan CN. Pro-resolving actions and stereoselective biosynthesis of 18S E-series resolvins in human leukocytes and murine inflammation. J Clin Invest. 2011;121(2):569–581.
39. Serhan CN, Petasis NA. Resolvins and protectins in inflammation-resolution. Chem Rev. 2011;111(10):5922–5943.
40. English JT, Norris PC, Hodges RR, Dartt DA, Serhan CN. Identification and profiling of specialized pro-resolving mediators in human tears by lipid mediator metabolomics. Prostaglandins Leukot Essent Fatty Acids. 2017;117:17–27.
41. Tungen JE, Aursnes M, Dalli J, Arnardottir H, Serhan CN, Hansen TV. Total synthesis of the anti-inflammatory and pro-resolving lipid mediator MaR1n-3 DPA utilizing an sp(3) -sp(3) Negishi cross-coupling reaction. Chemistry. 2014;20(45):14575–14578.
42. Rodriguez AR, Spur BW. Total synthesis of the macrophage derived anti-inflammatory lipid mediator Maresin 1. Tetrahedron Lett. 2012;53(32):4169–4172.
43. Rodriguez AR, Spur BW. Total synthesis of the anti-inflammatory lipid mediator Resolvin E2. Tetrahedron Lett. 2012;53:1912–1915.
44. Dona M, et al. Resolvin E1, an EPA-derived mediator in whole blood, selectively counterregulates leukocytes and platelets. Blood. 2008;112(3):848–855.
45. Fredman G, Serhan CN. Specialized proresolving mediator targets for RvE1 and RvD1 in peripheral blood and mechanisms of resolution. Biochem J. 2011;437(2):185–197.
46. El Kebir D, Gjorstrup P, Filep JG. Resolvin E1 promotes phagocytosis-induced neutrophil apoptosis and accelerates resolution of pulmonary inflammation. Proc Natl Acad Sci U S A. 2012;109(37):14983–14988.
47. Tjonahen E, et al. Resolvin E2: identification and anti-inflammatory actions: pivotal role of human 5-lipoxygenase in resolvin E series biosynthesis. Chem Biol. 2006;13(11):1193–1202.
48. Endo J, et al. 18-HEPE, an n-3 fatty acid metabolite released by macrophages, prevents pressure overload-induced maladaptive cardiac remodeling. J Exp Med. 2014;211(8):1673–1687.
49. Isobe Y, et al. Identification and structure determination of novel anti-inflammatory mediator resolvin E3, 17,18-dihydroxyeicosapentaenoic acid. JBiolChem. 2012;287(13):10525–10534.
50. Sawada Y, et al. Resolvin E1 inhibits dendritic cell migration in the skin and attenuates contact hypersensitivity responses. J Exp Med. 2015;212(11):1921–1930.
51. Oh SF, Dona M, Fredman G, Krishnamoorthy S, Irimia D, Serhan CN. Resolvin E2 formation and impact in inflammation resolution. JImmunol. 2012;188(9):4527–4534.
52. Dalli J, Serhan CN. Specific lipid mediator signatures of human phagocytes: microparticles stimulate macrophage efferocytosis and pro-resolving mediators. Blood. 2012;120(15):e60–e72.
53. Spite M, et al. Resolvin D2 is a potent regulator of leukocytes and controls microbial sepsis. Nature. 2009;461(7268):1287–1291.
54. Kasuga K, et al. Rapid appearance of resolvin precursors in inflammatory exudates: novel mechanisms in resolution. JImmunol. 2008;181(12):8677–8687.
55. Norris PC, Arnardottir H, Sanger JM, Fichtner D, Keyes GS, Serhan CN. Resolvin D3 multilevel proresolving actions are host protective during infection [published online ahead of print January 22, 2016]. Prostaglandins Leukot Essent Fatty Acids. https://doi.org/10.1016/ j.plefa.2016.01.001.
56. Winkler JW, et al. Structural insights into Resolvin D4 actions and further metabolites via a new total organic synthesis and validation [published online ahead of print January 29, 2018]. JLeukocBiol. https://doi.org/10.1002/JLB.3MI0617-254R.
57. Winkler JW, et al. Resolvin D4 stereoassignment and its novel actions in host protection and bacterial clearance. Sci Rep. 2016;6:18972.
58. Serhan CN, Dalli J, Colas RA, Winkler JW, Chiang N. Protectins and maresins: new pro-resolving families of mediators in acute inflammation and resolution bioactive metabolome. Biochim Biophys Acta. 2015;1851(4):397–413.
59. Katakura M, et al. Chronic arachidonic acid administration decreases docosahexaenoic acid- and eicosapentaenoic acid-derived metabolites in kidneys of aged rats. PLoS One. 2015;10(10):e0140884.
60. Yamada T, Tani Y, Nakanishi H, Taguchi R, Arita M, Arai H. Eosinophils promote resolution of acute periotonitis by producing proresolving mediators in mice. FASEB J. 2011;25(2):561–568.
61. Levy BD, et al. Protectin D1 is generated in asthma and dampens airway inflammation and hyper-responsiveness. J Immunol. 2007;178(1):496–502.
62. Miyata J, et al. Dysregulated synthesis of protectin D1 in eosinophils from patients with severe asthma. JAllergyClinImmunol. 2013;131(2):353–60.e1.
63. Masterson JC, et al. Eosinophil-mediated signalling attenuates inflammatory responses in experimental colitis. Gut. 2015;64(8):1236–1247.
64. White PJ, et al. Transgenic ω-3 PUFA enrichment alters morphology and gene expression profile in adipose tissue of obese mice: potential role for protectins. Metab Clin Exp. 2015;64(6):666–676.
65. Fonseca FC, Orlando RM, Turchetti-Maia RM, de Francischi JN. Comparative effects of the ω3 polyunsaturated fatty acid derivatives resolvins E1 and D1 and protectin DX in models of inflammation and pain. J Inflamm Res. 2017;10:119–133.
66. Stein K, et al. A role for 12/15-lipoxygenase-de-rived proresolving mediators in postoperative ileus: protectin DX-regulated neutrophil extrava-sation. J Leukoc Biol. 2016;99(2):231–239.
67. Bazan NG, Calandria JM, Serhan CN. Rescue and repair during photoreceptor cell renewal mediated by docosahexaenoic acid-derived neuroprotectin D1. J Lipid Res. 2010;51(8):2018–2031.
68. Asatryan A, Bazan NG. Molecular mechanisms of signaling via the docosanoid neuroprotectin D1 for cellular homeostasis and neuroprotection. JBiolChem. 2017;292(30):12390–12397.
69. Deng B, et al. Maresin biosynthesis and identification of maresin 2, a new anti-inflammatory and pro-resolving mediator from human macrophages. PLoS One. 2014;9(7):e102362.
70. Dalli J, et al. The novel 13S,14S-epoxy-maresin is converted by human macrophages to mares-in1 (MaR1), inhibits leukotriene A4 hydrolase (LTA4H), and shifts macrophage phenotype. FASEB J. 2013;27(7):2573–2583.
71. 2. JLipidRes. 2015;56(7):1248–1261.
72. Norling LV, Spite M, Yang R, Flower RJ, Perretti M, Serhan CN. Cutting edge: Humanized nano-proresolving medicines mimic inflammation-resolution and enhance wound healing. JImmunol. 2011;186(10):5543–5547.
73. Yates CM, Calder PC, Ed Rainger G. Pharmacology and therapeutics of omega-3 polyunsaturated fatty acids in chronic inflammatory disease. PharmacolTher. 2014;141(3):272–282.
74. Peltomaa E, Johnson MD, Taipale SJ. Marine cryptophytes are great sources of EPA and DHA. Mar Drugs. 2017;16(1):E3.
75. Jeansen S, Witkamp RF, Garthoff JA, van Helvoort A, Calder PC. Fish oil LC-PUFAs do not affect blood coagulation parameters and bleeding manifestations: analysis of 8 clinical studies with selected patient groups on omega-3enriched medical nutrition. Clin Nutr. 2018;37(30):948–957.
76. Chen CT, et al. Plasma non-esterified docosahexaenoic acid is the major pool supplying the brain. SciRep. 2015;5:15791.
77. Burdge GC, Jones AE, Wootton SA. Eicosapen-taenoic and docosapentaenoic acids are the principal products of alpha-linolenic acid metabolism in young men. Br J Nutr. 2002;88(4):355–363.
78. Markworth JF, et al. Divergent shifts in lipid mediator profile following supplementation with n-3 docosapentaenoic acid and eicosapentaenoic acid. FASEB J. 2016;30(11):3714–3725.
79. Vik A, Dalli J, Hansen TV. Recent advances in the chemistry and biology of anti-inflammatory and specialized pro-resolving mediators biosynthesized from n-3 docosapentaenoic acid. Bioorg Med Chem Lett. 2017;27(11):2259–2266.
80. Gobbetti T, et al. Protectin D1n-3 DPAand resolvin D5n-3 DPAare effectors of intestinal protection. Proc Natl Acad Sci U S A. 2017;114(15):3963–3968.
81. Serhan CN. Lipoxins and aspirin-triggered 15-epi-lipoxins are the first lipid mediators of endogenous anti-inflammation and resolution. Prostaglandins Leukot Essent Fatty Acids. 2005;73(3–4):141–162.
82. Lee CR, Zeldin DC. Resolvin infectious inflammation by targeting the host response. N Engl J Med. 2015;373(22):2183–2185.
83. Tsuda S, et al. Novel mechanism of regulation of the 5-lipoxygenase/leukotriene B4pathway by high-density lipoprotein in macrophages. SciRep. 2017;7(1):12989.
84. Serhan CN, Savill J. Resolution of inflammation: the beginning programs the end. Nat Immunol. 2005;6(12):1191–1197.
85. Schwab JM, Chiang N, Arita M, Serhan CN. Resolvin E1 and protectin D1 activate inflammation-resolution programmes. Nature. 2007;447(7146):869–874.
86. Arnardottir HH, Dalli J, Colas RA, Shinohara M, Serhan CN. Aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines. JImmunol. 2014;193(8):4235–4244.
87. Luo B, et al. Phagocyte respiratory burst activates macrophage erythropoietin signalling to promote acute inflammation resolution. Nat Commun. 2016;7:12177.
88. Sugimoto MA, et al. Plasmin and plasminogen induce macrophage reprogramming and regulate key steps of inflammation resolution via annexin A1. Blood. 2017;129(21):2896–2907.
89. Chiang N, et al. Inhaled carbon monoxide accelerates resolution of inflammation via unique pro-resolving mediator — heme oxygenase-1 circuits. J Immunol. 2013;190(12):6378–6388.
90. Rossi AG, et al. Cyclin-dependent kinase inhibitors enhance the resolution of inflammation by promoting inflammatory cell apoptosis. Nat Med. 2006;12(9):1056–1064.
91. Perretti M, et al. Endogenous lipid- and peptide-derived anti-inflammatory pathways generated with glucocorticoid and aspirin treatment activate the lipoxin A4 receptor. Nat Med. 2002;8(11):1296–1302.
92. Gilroy DW, Colville-Nash PR, Willis D, Chivers J, Paul-Clark MJ, Willoughby DA. Inducible cyclox-ygenase may have anti-inflammatory properties. Nat Med. 1999;5(6):698–701.
93. Markworth JF, et al. Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment. Am J Physiol Regul Integr Comp Physiol. 2013;305(11):R1281–R1296.
94. Chiang N, Schwab JM, Fredman G, Kasuga K, Gelman S, Serhan CN. Anesthetics impact the resolution of inflammation. PLoS One. 2008;3(4):e1879.
95. Perretti M, Leroy X, Bland EJ, Montero-Melendez T. Resolution pharmacology: opportunities for therapeutic innovation in inflammation. Trends PharmacolSci. 2015;36(11):737–755.
96. Abdulnour RE, et al. Aspirin-triggered resolvin D1 is produced during self-resolving gram-negative bacterial pneumonia and regulates host immune responses for the resolution of lung inflammation. MucosalImmunol. 2016;9(5):1278–1287.
97. Chiang N, Dalli J, Colas RA, Serhan CN. Identification of resolvin D2 receptor mediating resolution of infections and organ protection. JExp Med. 2015;212(8):1203–1217.
98. Abdulnour RE, et al. Maresin 1 biosynthesis during platelet-neutrophil interactions is organ-protective. Proc Natl Acad Sci U S A. 2014;111(46):16526–16531.
99. Colby JK, et al. Resolvin D3 and aspirin-triggered resolvin D3 are protective for injured epithelia. Am J Pathol. 2016;186(7):1801–1813.
100. Eickmeier O, et al. Aspirin-triggered resolvin D1 reduces mucosal inflammation and promotes resolution in a murine model of acute lung injury. MucosalImmunol. 2013;6(2):256–266.
101. Titos E, et al. Signaling and immunoresolving actions of resolvin D1 in inflamed human visceral adipose tissue. JImmunol. 2016;197(8):3360–3370.
102. Levy BD, Serhan CN. Resolution of acute inflammation in the lung. Annu Rev Physiol. 2014;76:467–492.
103. Barnig C, et al. Lipoxin A4 regulates natural killer cell and type 2 innate lymphoid cell activation in asthma. Sci Transl Med. 2013;5(174):174ra26.
104. Krishnamoorthy N, et al. Cutting edge: maresin-1 engages regulatory T cells to limit type 2 innate lymphoid cell activation and promote resolution of lung inflammation. J Immunol. 2015;194(3):863–867.
105. Chiurchiù V, et al. Proresolving lipid mediators resolvin D1, resolvin D2, and maresin 1 are critical in modulating T cell responses. SciTransl Med. 2016;8(353):353ra111.
106. Ramon S, Gao F, Serhan CN, Phipps RP. Specialized proresolving mediators enhance human B cell differentiation to antibody-secreting cells. J Immunol. 2012;189(2):1036–1042.
107. Kim N, Ramon S, Thatcher TH, Woeller CF, Sime PJ, Phipps RP. Specialized proresolving mediators (SPMs) inhibit human B-cell IgE production. Eur J Immunol. 2016;46(1):81–91.
108. Krishnamoorthy S, et al. Resolvin D1 binds human phagocytes with evidence for pro-resolving receptors. ProcNatlAcadSciUSA. 2010;107(4):1660–1665.
109. Norling LV, Dalli J, Flower RJ, Serhan CN, Perretti M. Resolvin D1 limits polymorphonuclear leukocytes recruitment to inflammatory loci: receptor dependent actions. Arterioscler Thromb Vasc Biol. 2012;32(8):1970–1978.
110. Arita M, Ohira T, Sun YP, Elangovan S, Chiang N, Serhan CN. Resolvin E1 selectively interacts with leukotriene B4 receptor BLT1 and ChemR23 to regulate inflammation. JImmunol. 2007;178(6):3912–3917.
111. Colas RA, et al. Identification and actions of the maresin 1 metabolome in infectious inflammation. J Immunol. 2016;197(11):4444–4452.
112. He R, Sang H, Ye RD. Serum amyloid A induces IL-8 secretion through a G protein-coupled receptor, FPRL1/LXA4R. Blood. 2003;101(4):1572–1581.
113. Bozinovski S, et al. Serum amyloid A opposes lipoxin A(4) to mediate glucocorticoid refractory lung inflammation in chronic obstructive pulmonary disease. Proc Natl Acad Sci U S A. 2012;109(3):935–940.
114. m. Ligand-specific conformational change of the G-protein-coupled receptor ALX/FPR2 determines proresolving functional responses. Proc Natl Acad Sci U S A. 2013;110(45):18232–18237.
115. Pamplona FA, et al. Anti-inflammatory lipoxin A4 is an endogenous allosteric enhancer of CB1 cannabinoid receptor. Proc Natl Acad Sci U S A. 2012;109(51):21134–21139.
116. Norris PC, Libreros S, Chiang N, Serhan CN. A cluster of immunoresolvents links coagulation to innate host defense in human blood. Sci Signal. 2017;10(490):eaan1471.
117. Chiang N, de la Rosa X, Libreros S, Serhan CN. Novel resolvin D2 receptor axis in infectious inflammation. JImmunol. 2017;198(2):842–851.
118. Haworth O, Cernadas M, Yang R, Serhan CN, Levy BD. Resolvin E1 regulates interleukin 23, interferon-gamma and lipoxin A4 to promote the resolution of allergic airway inflammation. Nat Immunol. 2008;9(8):873–879.
119. Carlo T, Kalwa H, Levy BD. 15-Epi-lipoxin A4 inhibits human neutrophil superoxide anion generation by regulating polyisoprenyl diphosphate phosphatase 1. FASEB J. 2013;27(7):2733–2741.
120. Bisicchia E, et al. Resolvin D1 halts remote neuroinflammation and improves functional recovery after focal brain damage via ALX/FPR2 receptor-regulated microRNAs [published online ahead of print January 22, 2018]. MolNeurobiol. https://doi.org/10.1007/s12035-018-0889-z.
121. Fredman G, Li Y, Dalli J, Chiang N, Serhan CN. Self-limited versus delayed resolution of acute inflammation: temporal regulation of pro-resolving mediators and microRNA. SciRep. 2012;2:639.
122. Recchiuti A, et al. Immunoresolving actions of oral resolvin D1 include selective regulation of the transcription machinery in resolution-phase mouse macrophages. FASEB J. 2014;28(7):3090–3102.
123. Zhu M, et al. Pro-resolving lipid mediators improve neuronal survival and increase Aβ42 phagocytosis. MolNeurobiol. 2016;53(4):2733–2749.
124. Nielsen MM, et al. Mass spectrometry imaging of biomarker lipids for phagocytosis and signalling during focal cerebral ischaemia. SciRep. 2016;6:39571.
125. Fiala M, Terrando N, Dalli J. Specialized proresolving mediators from omega-3 fatty acids improve amyloid-β phagocytosis and regulate inflammation in patients with minor cognitive impairment. J Alzheimers Dis. 2015;48(2):293–301.
126. Wang X, et al. Resolution of inflammation is altered in Alzheimer’s disease. Alzheimers Dement. 2015;11(1):40–50.e42.
127. Francos-Quijorna I, et al. Maresin 1 promotes inflammatory resolution, neuroprotection, and functional neurological recovery after spinal cord injury. JNeurosci. 2017;37(48):11731–11743.
128. Mukherjee PK, Marcheselli VL, Serhan CN, Bazan NG. Neuroprotectin D1: a docosahexaenoic acid-derived docosatriene protects human retinal pigment epithelial cells from oxidative stress. Proc Natl Acad Sci U S A. 2004;101(22):8491–8496.
129. Belayev L, et al. Neuroprotectin D1 upregulates Iduna expression and provides protection in cellular uncompensated oxidative stress and in experimental ischemic stroke. CellDeathDiffer. 2017;24(6):1091–1099.
130. Rajasagi NK, Bhela S, Varanasi SK, Rouse BT. Frontline Science: Aspirin-triggered resolvin D1 controls herpes simplex virus-induced corneal immunopathology. J Leukoc Biol. 2017;102(5):1159–1171.
131. Deyama S, et al. Resolvin D1 and D2 reverse lipo-polysaccharide-induced depression-like behaviors through the mTORC1 signaling pathway. Int J Neuropsychopharmacol. 2017;20(7):575–584.
132. Ishikawa Y, et al. Rapid and sustained antidepressant effects of resolvin D1 and D2 in a chronic unpredictable stress model. Behav Brain Res. 2017;332:233–236.
133. Ji RR, Xu ZZ, Strichartz G, Serhan CN. Emerging roles of resolvins in the resolution of inflammation and pain. Trends Neurosci. 2011;34(11):599–609.
134. Xu ZZ, et al. Resolvins RvE1 and RvD1 attenuate inflammatory pain via central and peripheral actions. NatMed. 2010;16(5):592–597.
135. Park CK, Xu ZZ, Liu T, Lü N, Serhan CN, Ji RR. Resolvin D2 is a potent endogenous inhibitor for transient receptor potential subtype V1/A1, inflammatory pain, and spinal cord synaptic plasticity in mice: distinct roles of resolvin D1, D2, and E1. J Neurosci. 2011;31(50):18433–18438.
136. Park CK, Lü N, Xu ZZ, Liu T, Serhan CN, Ji RR. Resolving TRPV1 and TNF-α-mediated spinal cord synaptic plasticity and inflammatory pain with neuroprotectin D1. JNeurosci. 2011;31(42):15072–15085.
137. Jo YY, Lee JY, Park CK. Resolvin E1 inhibits substance P-induced potentiation of TRPV1 in primary sensory neurons. Mediators Inflamm. 2016;2016:5259321.
138. Harrison JL, et al. Resolvins AT-D1 and E1 differentially impact functional outcome, post-traumatic sleep, and microglial activation following diffuse brain injury in the mouse. Brain Behav Immun. 2015;47:131–140.
139. Meesawatsom P, Burston J, Hathway G, Bennett A, Chapman V. Inhibitory effects of aspirin-triggered resolvin D1 on spinal nociceptive processing in rat pain models. J Neuroinflammation. 2016;13(1):233.
140. Lima-Garcia JF, Dutra RC, da Silva K, Motta EM, Campos MM, Calixto JB. The precursor of resolvin D series and aspirin-triggered resolvin D1 display anti-hyperalgesic properties in adjuvant-induced arthritis in rats. Br J Pharmacol. 2011;164(2):278–293.
141. Huang J, et al. Targeting the D-series resolvin receptor system for the treatment of osteoarthritic pain. Arthritis Rheumatol. 2017;69(5):996–1008.
142. Tedeschi SK, Bathon JM, Giles JT, Lin TC, Yoshida K, Solomon DH. Relationship between fish consumption and disease activity in rheumatoid arthritis. Arthritis Care Res (Hoboken). 2018;70(3):327–332.
143. Barden AE, Moghaddami M, Mas E, Phillips M, Cleland LG, Mori TA. Specialised pro-resolving mediators of inflammation in inflammatory arthritis. Prostaglandins Leukot Essent Fatty Acids. 2016;107:24–29.
144. Arnardottir HH, Dalli J, Norling LV, Colas RA, Perretti M, Serhan CN. Resolvin D3 is dysregu-lated in arthritis and reduces arthritic inflammation. JImmunol. 2016;197(6):2362–2368.
145. Norling LV, et al. Proresolving and cartilage-protective actions of resolvin D1 in inflammatory arthritis. JCIInsight. 2016;1(5):e85922.
146. Valdes AM, et al. Association of the resolvin precursor 17-HDHA, but not D- or E- series resolvins, with heat pain sensitivity and osteoarthritis pain in humans. Sci Rep. 2017;7(1):10748.
147. Koopman FA, et al. Vagus nerve stimulation inhibits cytokine production and attenuates disease severity in rheumatoid arthritis. Proc Natl Acad Sci U S A. 2016;113(29):8284–8289.
148. Mirakaj V, Dalli J, Granja T, Rosenberger P, Serhan CN. Vagus nerve controls resolution and pro-resolving mediators of inflammation. JExp Med. 2014;211(6):1037–1048.
149. Dalli J, Colas RA, Arnardottir H, Serhan CN. Vagal regulation of group 3 innate lymphoid cells and the immunoresolvent PCTR1 controls infection resolution. Immunity. 2017;46(1):92–105.
150. Colas RA, Shinohara M, Dalli J, Chiang N, Serhan CN. Identification and signature profiles for pro-resolving and inflammatory lipid mediators in human tissue. Am J Physiol Cell Physiol. 2014;307(1):C39–C54.
151. Hong S, Tjonahen E, Morgan EL, Lu Y, Serhan CN, Rowley AF. Rainbow trout (Oncorhynchus mykiss) brain cells biosynthesize novel docosahexaenoic acid-derived resolvins and protectins-mediator lipidomic analysis. Prostaglandins Other Lipid Mediat. 2005;78(1–4):107–116.
152. Raatz SK, et al. Baking reduces prostaglandin, resolvin, and hydroxy-fatty acid content of farm-raised Atlantic salmon (Salmo salar). J Agric Food Chem. 2011;59(20):11278–11286.
153. Mas E, Croft KD, Zahra P, Barden A, Mori TA. Resolvins D1, D2, and other mediators of self-limited resolution of inflammation in human blood following n-3 fatty acid supplementation. Clin Chem. 2012;58(10):1476–1484.
154. Barden AE, Mas E, Mori TA. n-3 Fatty acid supplementation and proresolving mediators of inflammation. CurrOpinLipidol. 2016;27(1):26–32.
155. Fredman G, et al. An imbalance between specialized pro-resolving lipid mediators and pro-inflammatory leukotrienes promotes instability of atherosclerotic plaques. Nat Commun. 2016;7:12859.
156. Sasaki A, et al. Determination of ω-6 and ω-3 PUFA metabolites in human urine samples using UPLC/MS/MS. AnalBioanalChem. 2015;407(6):1625–1639.
157. Rathod KS, et al. Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans. J Clin Invest. 2017;127(1):169–182.
158. Ramsden CE, et al. Targeted alteration of dietary n-3 and n-6 fatty acids for the treatment of chronic headaches: a randomized trial. Pain. 2013;154(11):2441–2451.
159. Dalli J, et al. Human sepsis eicosanoid and proresolving lipid mediator temporal profiles: correlations with survival and clinical outcomes. Crit Care Med. 2017;45(1):58–68.
160. See VHL, et al. Effects of prenatal n-3 fatty acid supplementation on offspring resolvins at birth and 12 years of age: a double-blind, randomised controlled clinical trial. Br J Nutr. 2017;118(11):971–980.
161. See VHL, et al. Effects of postnatal omega-3 fatty acid supplementation on offspring pro-resolving mediators of inflammation at 6 months and 5 years of age: a double blind, randomized controlled clinical trial. Prostaglandins Leukot Essent Fatty Acids. 2017;126:126–132.
162. Keelan JA, et al. Effects of maternal n-3 fatty acid supplementation on placental cytokines, pro-resolving lipid mediators and their precursors. Reproduction. 2015;149(2):171–178.
163. Mozurkewich EL, et al. Pathway markers for pro-resolving lipid mediators in maternal and umbilical cord blood: a secondary analysis of the Mothers, Omega-3, and Mental Health Study. FrontPharmacol. 2016;7:274.
164. Elliott E, Hanson CK, Anderson-Berry AL, Nordgren TM. The role of specialized pro-resolving mediators in maternal-fetal health. Prostaglandins LeukotEssentFattyAcids. 2017;126:98–104.
165. Arnardottir H, Orr SK, Dalli J, Serhan CN. Human milk proresolving mediators stimulate resolution of acute inflammation. MucosalImmunol. 2016;9(3):757–766.
166. Weiss GA, Troxler H, Klinke G, Rogler D, Braegger C, Hersberger M. 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. 2013;12:89.
167. Ramaswami R, Serhan CN, Levy BD, Makrides M. Fish oil supplementation in pregnancy. NEngl JMed. 2016;375(26):2599–2601.
168. Arita M, et al. Metabolic inactivation of resolvin E1 and stabilization of its anti-inflammatory actions. J Biol Chem. 2006;281(32):22847–22854.
169. De Caterina R. n-3 Fatty acids in cardiovascular disease. N Engl J Med. 2011;364(25):2439–2450.
170. Del Gobbo LC, et al. ω-3 Polyunsaturated fatty acid biomarkers and coronary heart disease: pooling project of 19 cohort studies. JAMAIntern Med. 2016;176(8):1155–1166.
171. Back M. Omega-3 fatty acids in atherosclerosis and coronary artery disease. Future Sci OA. 2017;3(4):Fso236.
172. Elabdeen HR, Mustafa M, Szklenar M, Rühl R, Ali R, Bolstad AI. Ratio of pro-resolving and pro-inflammatory lipid mediator precursors as potential markers for aggressive periodontitis. PLoSOne. 2013;8(8):e70838.
173. Barden AE, et al. A randomized trial of effects of alcohol on cytochrome P450 eicosanoids, mediators of inflammation resolution, and blood pressure in men. Alcohol Clin Exp Res. 2017;41(10):1666–1674.
174. Polus A, et al. Omega-3 fatty acid supplementation influences the whole blood transcriptome in women with obesity, associated with proresolving lipid mediator production. Biochim Biophys Acta. 2016;1861(11):1746–1755.
175. Hecker M, et al. Immunomodulation by lipid emulsions in pulmonary inflammation: a randomized controlled trial. Crit Care. 2015;19:226.
176. de la Rosa X, Norris PC, Chiang N, Rodriguez AR, Spur BW, Serhan CN. Identification and complete stereochemical assignments of the new Resolvin Conjugates in Tissue Regeneration (RCTR) in human tissues that stimulate proresolving phagocyte functions and tissue regeneration. Am J Pathol. 2018;188(4):950–966.
177. Clish CB, Levy BD, Chiang N, Tai HH, Serhan CN. Oxidoreductases in lipoxin A4 metabolic inactivation: a novel role for 15-onoprostaglandin 13-reductase/leukotriene B4 12-hydroxydehy-drogenase in inflammation. JBiolChem. 2000;275(33):25372–25380.
178. Lance KD, et al. Unidirectional and sustained delivery of the proresolving lipid mediator resolvin D1 from a biodegradable thin film device. J Biomed Mater Res A. 2017;105(1):31–41.
179. Orr SK, Colas RA, Dalli J, Chiang N, Serhan CN. Proresolving actions of a new resolvin D1 analog mimetic qualifies as an immunoresolvent. Am J Physiol Lung Cell Mol Physiol. 2015;308(9):L904–L911.
180. Resolvyx Pharmaceuticals Inc. Safety and efficacy study of RX-10045 on the signs and symptoms of dry eye. ClinicalTrials.gov Website. https://clinicaltrials.gov/ct2/show/NCT00799552. Accessed March 27, 2018.
181. Science Blog. Resolvyx announces positive data — phase 2 trial of resolvin RX-10045 for dry eye syndrome. https://scienceblog.com/24358/ resolvyx-announces-positive-data-phase-2-trial-of-resolvin-rx-10045-for-dry-eye-syndrome/. 2009.
182. The Forsyth Institute. Safety and Preliminary Efficacy of Lipoxin Analog BLXA4-ME Oral Rinse for the Treatment of Gingivitis (BLXA4). ClinicalTrials.gov Website. https://clinicaltrials.gov/ct2/show/NCT02342691. Accessed March 27, 2018.
183. Reátegui E, et al. Microscale arrays for the profiling of start and stop signals coordinating human-neutrophil swarming. NatBiomedEng. 2017;1:0094.
184. Motwani MP, et al. Potent anti-inflammatory and pro-resolving effects of anabasum in a human model of self-resolving acute inflammation [published online ahead of print December 14, 2017]. Clin Pharmacol Ther. https://doi.org/10.1002/cpt.980.
185. Hu J, et al. Dexmedetomidine prevents cognitive decline by enhancing resolution of high mobility group box 1 protein-induced inflammation through a vagomimetic action in mice [published online ahead of print December 18, 2017]. Anesthesiology. https://doi.org/10.1097/ALN.0000000000002038.
186. Uno H, et al. Immunonutrition suppresses acute inflammatory responses through modulation of resolvin E1 in patients undergoing major hepatobiliary resection. Surgery. 2016;160(1):228–236.
187. Elajami TK, Colas RA, Dalli J, Chiang N, Serhan CN, Welty FK. Specialized proresolving lipid mediators in patients with coronary artery disease and their potential for clot remodeling. FASEB J. 2016;30(8):2792–2801.
188. Erdman J, Oria M, Pillsbury L, eds. Nutrition and traumatic brain injury: improving acute and subacute health outcomes in military personnel. Washington, DC, USA: National Academies Press; 2011.
189. Sulciner ML, et al. Resolvins suppress tumor growth and enhance cancer therapy. JExpMed. 2018;215(1):115–140.
190. Zhong X, Lee HN, Surh YJ. RvD1 inhibits TNFα-induced c-Myc expression in normal intestinal epithelial cells and destabilizes hyper-expressed c-Myc in colon cancer cells. Biochem Biophys Res Commun. 2018;496(2):316–323.
191. Christ A, et al. Western diet triggers NLRP3-dependent innate immune reprogramming. Cell. 2018;172(1–2):162–175.e14.
192. Lee S, et al. NLRP3 inflammasome deficiency protects against microbial sepsis via increased lipoxin B4 synthesis. Am J Respir Crit Care Med. 2017;196(6):713–726.
193. López-Vicario C, et al. Association of a variant in the gene encoding for ERV1/ChemR23 with reduced inflammation in visceral adipose tissue from morbidly obese individuals. SciRep. 2017;7(1):15724.
194. Gromovsky AD, et al. Δ-5 fatty acid desaturase FADS1 impacts metabolic disease by balancing proinflammatory and proresolving lipid mediators. Arterioscler Thromb Vasc Biol. 2018;38(1):218–231.
195. Lee CT, et al. Resolvin E1 reverses experimental periodontitis and dysbiosis. JImmunol. 2016;197(7):2796–2806.
196. Arita M, et al. Resolvin E1, an endogenous lipid mediator derived from omega-3 eicosapentaenoic acid, protects against 2,4,6-trinitrobenzene sul-fonic acid-induced colitis. ProcNatlAcadSciUSA. 2005;102(21):7671–7676.
197. Bohr S, Patel SJ, Sarin D, Irimia D, Yarmush ML, Berthiaume F. Resolvin D2 prevents secondary thrombosis and necrosis in a mouse burn wound model. Wound Repair Regen. 2013;21(1):35–43.
198. Eritja N, et al. Tumour-microenvironmental blood flow determines a metabolomic signature identifying lysophospholipids and resolvin D as biomarkers in endometrial cancer patients. Oncotarget. 2017;8(65):109018–109026.
199. Prevete N, et al. Formyl peptide receptor 1 suppresses gastric cancer angiogenesis and growth by exploiting inflammation resolution pathways. Oncoimmunology. 2017;6(4):e1293213.
200. Hersberger M. Potential role of the lipoxygenase derived lipid mediators in atherosclerosis: leukotrienes, lipoxins and resolvins. Clin Chem Lab Med. 2010;48(8):1063–1073.