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Systematic Understanding of Bioactive Lipids in Neuro-Immune Interactions: Lessons from an Animal Model of Multiple Sclerosis

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The Role of Bioactive Lipids in Cancer, Inflammation and Related Diseases

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1161))

Abstract

Bioactive lipids, or lipid mediators, are utilized for intercellular communications. They are rapidly produced in response to various stimuli and exported to extracellular spaces followed by binding to cell surface G protein-coupled receptors (GPCRs) or nuclear receptors. Many drugs targeting lipid signaling such as non-steroidal anti-inflammatory drugs (NSAIDs), prostaglandins, and antagonists for lipid GPCRs are in use. For example, the sphingolipid analog, fingolimod (also known as FTY720), was the first oral disease-modifying therapy (DMT) for relapsing-remitting multiple sclerosis (MS), whose mechanisms of action (MOA) includes sequestration of pathogenic lymphocytes into secondary lymphoid organs, as well as astrocytic modulation, via down-regulation of the sphingosine 1-phosphate (S1P) receptor, S1P1, by in vivo-phosphorylated fingolimod. Though the cause of MS is still under debate, MS is considered to be an autoimmune demyelinating and neurodegenerative disease. This review summarizes the involvement of bioactive lipids (prostaglandins, leukotrienes, platelet-activating factors, lysophosphatidic acid, and S1P) in MS and the animal model, experimental autoimmune encephalomyelitis (EAE). Genetic ablation, along with pharmacological inhibition, of lipid metabolic enzymes and lipid GPCRs revealed that each bioactive lipid has a unique role in regulating immune and neural functions, including helper T cell (TH1 and TH17) differentiation and proliferation, immune cell migration, astrocyte responses, endothelium function, and microglial phagocytosis. A systematic understanding of bioactive lipids in MS and EAE dredges up information about understudied lipid signaling pathways, which should be clarified in the near future to better understand MS pathology and to develop novel DMTs.

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References

  1. Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC (2006) CNS immune privilege: hiding in plain sight. Immunol Rev 213:48–65

    Article  PubMed  PubMed Central  Google Scholar 

  2. Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J (2015) Structural and functional features of central nervous system lymphatic vessels. Nature 523:337–341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Herisson F, Frodermann V, Courties G, Rohde D, Sun Y, Vandoorne K, Wojtkiewicz GR, Masson GS, Vinegoni C, Kim J, Kim DE, Weissleder R, Swirski FK, Moskowitz MA, Nahrendorf M (2018) Direct vascular channels connect skull bone marrow and the brain surface enabling myeloid cell migration. Nat Neurosci 21:1209–1217

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Arima Y, Harada M, Kamimura D, Park JH, Kawano F, Yull FE, Kawamoto T, Iwakura Y, Betz UA, Marquez G, Blackwell TS, Ohira Y, Hirano T, Murakami M (2012) Regional neural activation defines a gateway for autoreactive T cells to cross the blood-brain barrier. Cell 148:447–457

    Article  CAS  PubMed  Google Scholar 

  5. Da Mesquita S, Louveau A, Vaccari A, Smirnov I, Cornelison RC, Kingsmore KM, Contarino C, Onengut-Gumuscu S, Farber E, Raper D, Viar KE, Powell RD, Baker W, Dabhi N, Bai R, Cao R, Hu S, Rich SS, Munson JM, Lopes MB, Overall CC, Acton ST, Kipnis J (2018) Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease. Nature 560:185–191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Filiano AJ, Xu Y, Tustison NJ, Marsh RL, Baker W, Smirnov I, Overall CC, Gadani SP, Turner SD, Weng Z, Peerzade SN, Chen H, Lee KS, Scott MM, Beenhakker MP, Litvak V, Kipnis J (2016) Unexpected role of interferon-gamma in regulating neuronal connectivity and social behaviour. Nature 535:425–429

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Hickey WF (1999) The pathology of multiple sclerosis: a historical perspective. J Neuroimmunol 98:37–44

    Article  CAS  PubMed  Google Scholar 

  8. Murray TJ (2009) The history of multiple sclerosis: the changing frame of the disease over the centuries. J Neurol Sci 277(Suppl 1):S3–S8

    Article  PubMed  Google Scholar 

  9. Young IR, Hall AS, Pallis CA, Legg NJ, Bydder GM, Steiner RE (1981) Nuclear magnetic resonance imaging of the brain in multiple sclerosis. Lancet 2:1063–1066

    Article  CAS  PubMed  Google Scholar 

  10. Mcdonald WI, Compston A, Edan G, Goodkin D, Hartung HP, Lublin FD, Mcfarland HF, Paty DW, Polman CH, Reingold SC, Sandberg-Wollheim M, Sibley W, Thompson A, Van Den Noort S, Weinshenker BY, Wolinsky JS (2001) Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 50:121–127

    Article  CAS  PubMed  Google Scholar 

  11. Thompson AJ, Banwell BL, Barkhof F, Carroll WM, Coetzee T, Comi G, Correale J, Fazekas F, Filippi M, Freedman MS, Fujihara K, Galetta SL, Hartung HP, Kappos L, Lublin FD, Marrie RA, Miller AE, Miller DH, Montalban X, Mowry EM, Sorensen PS, Tintore M, Traboulsee AL, Trojano M, Uitdehaag BMJ, Vukusic S, Waubant E, Weinshenker BG, Reingold SC, Cohen JA (2018) Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol 17:162–173

    Article  PubMed  Google Scholar 

  12. Kurtzke JF (1983) Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology 33:1444–1452

    Article  CAS  PubMed  Google Scholar 

  13. Kurtzke JF (2015) On the origin of EDSS. Mult Scler Relat Disord 4:95–103

    Article  PubMed  Google Scholar 

  14. Medaer R (1979) Does the history of multiple sclerosis go back as far as the 14th century? Acta Neurol Scand 60:189–192

    Article  CAS  PubMed  Google Scholar 

  15. Leray E, Moreau T, Fromont A, Edan G (2016) Epidemiology of multiple sclerosis. Rev Neurol (Paris) 172:3–13

    Article  CAS  Google Scholar 

  16. Lancet T (2018) End of the road for daclizumab in multiple sclerosis. Lancet 391:1000

    Google Scholar 

  17. Derfuss T, Kuhle J, Lindberg R, Kappos L (2013) Natalizumab therapy for multiple sclerosis. Semin Neurol 33:26–36

    Article  PubMed  Google Scholar 

  18. Willis MD, Robertson NP (2016) Alemtuzumab for multiple sclerosis. Curr Neurol Neurosci Rep 16:84

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X, Rammohan KW, Selmaj K, Traboulsee A, Wolinsky JS, Arnold DL, Klingelschmitt G, Masterman D, Fontoura P, Belachew S, Chin P, Mairon N, Garren H, Kappos L, Opera I, Investigators OIC (2017) Ocrelizumab versus interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med 376:221–234

    Article  CAS  PubMed  Google Scholar 

  20. Jakimovski D, Kolb C, Ramanathan M, Zivadinov R, Weinstock-Guttman B (2018) Interferon beta for multiple sclerosis. Cold Spring Harb Perspect Med 8:a032003

    Article  PubMed  PubMed Central  Google Scholar 

  21. Chun J, Brinkmann V (2011) A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med 12:213–228

    PubMed  PubMed Central  Google Scholar 

  22. Cohen JA, Chun J (2011) Mechanisms of fingolimod’s efficacy and adverse effects in multiple sclerosis. Ann Neurol 69:759–777

    Article  CAS  PubMed  Google Scholar 

  23. Kihara Y, Groves A, Rivera RR, Chun J (2015a) Dimethyl fumarate inhibits integrin alpha4 expression in multiple sclerosis models. Ann Clin Transl Neurol 2:978–983

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Von Glehn F, Dias-Carneiro RPC, Moraes AS, Farias AS, Silva V, Oliveira FTM, Silva C, De Carvalho F, Rahal E, Baecher-Allan C, Santos LMB (2018) Dimethyl fumarate downregulates the immune response through the HCA2/GPR109A pathway: implications for the treatment of multiple sclerosis. Mult Scler Relat Disord 23:46–50

    Article  PubMed  Google Scholar 

  25. Groves A, Kihara Y, Chun J (2013) Fingolimod: direct CNS effects of sphingosine 1-phosphate (S1P) receptor modulation and implications in multiple sclerosis therapy. J Neurol Sci 328:9–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rothhammer V, Mascanfroni ID, Bunse L, Takenaka MC, Kenison JE, Mayo L, Chao CC, Patel B, Yan R, Blain M, Alvarez JI, Kebir H, Anandasabapathy N, Izquierdo G, Jung S, Obholzer N, Pochet N, Clish CB, Prinz M, Prat A, Antel J, Quintana FJ (2016) Type I interferons and microbial metabolites of tryptophan modulate astrocyte activity and central nervous system inflammation via the aryl hydrocarbon receptor. Nat Med 22:586–597

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Al-Jaderi Z, Maghazachi AA (2016) Utilization of Dimethyl Fumarate and related molecules for treatment of multiple sclerosis, cancer, and other diseases. Front Immunol 7:278

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Rivers TM, Sprunt DH, Berry GP (1933) Observations on Attempts to Produce Acute Disseminated Encephalomyelitis in Monkeys. J Exp Med 58:39–53

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Paterson PY (1960) Transfer of allergic encephalomyelitis in rats by means of lymph node cells. J Exp Med 111:119–136

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ben-Nun A, Wekerle H, Cohen IR (1981) Vaccination against autoimmune encephalomyelitis with T-lymphocyte line cells reactive against myelin basic protein. Nature 292:60–61

    Article  CAS  PubMed  Google Scholar 

  31. Zamvil SS, Mitchell DJ, Moore AC, Kitamura K, Steinman L, Rothbard JB (1986) T-cell epitope of the autoantigen myelin basic protein that induces encephalomyelitis. Nature 324:258–260

    Article  CAS  PubMed  Google Scholar 

  32. Rangachari M, Kuchroo VK (2013) Using EAE to better understand principles of immune function and autoimmune pathology. J Autoimmun 45:31–39

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Windhagen A, Nicholson LB, Weiner HL, Kuchroo VK, Hafler DA (1996) Role of Th1 and Th2 cells in neurologic disorders. Chem Immunol 63:171–186

    CAS  PubMed  Google Scholar 

  34. Langrish CL, Chen Y, Blumenschein WM, Mattson J, Basham B, Sedgwick JD, Mcclanahan T, Kastelein RA, Cua DJ (2005) IL-23 drives a pathogenic T cell population that induces autoimmune inflammation. J Exp Med 201:233–240

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yu CY, Whitacre CC (2004) Sex, MHC and complement C4 in autoimmune diseases. Trends Immunol 25:694–699

    Article  CAS  PubMed  Google Scholar 

  36. Kihara Y, Ishii S, Kita Y, Toda A, Shimada A, Shimizu T (2005) Dual phase regulation of experimental allergic encephalomyelitis by platelet-activating factor. J Exp Med 202:853–863

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Kihara Y, Matsushita T, Kita Y, Uematsu S, Akira S, Kira J, Ishii S, Shimizu T (2009) Targeted lipidomics reveals mPGES-1-PGE2 as a therapeutic target for multiple sclerosis. Proc Natl Acad Sci U S A 106:21807–21812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kihara Y, Yanagida K, Masago K, Kita Y, Hishikawa D, Shindou H, Ishii S, Shimizu T (2008) Platelet-activating factor production in the spinal cord of experimental allergic encephalomyelitis mice via the group IVA cytosolic phospholipase A2-lyso-PAFAT axis. J Immunol 181:5008–5014

    Article  CAS  PubMed  Google Scholar 

  39. Kihara Y, Yokomizo T, Kunita A, Morishita Y, Fukayama M, Ishii S, Shimizu T (2010) The leukotriene B4 receptor, BLT1, is required for the induction of experimental autoimmune encephalomyelitis. Biochem Biophys Res Commun 394:673–678

    Article  CAS  PubMed  Google Scholar 

  40. Terry RL, Ifergan I, Miller SD (2016) Experimental autoimmune encephalomyelitis in Mice. Methods Mol Biol 1304:145–160

    Article  PubMed  PubMed Central  Google Scholar 

  41. Groves A, Kihara Y, Jonnalagadda D, Rivera R, Kennedy G, Mayford M, Chun J (2018) A functionally defined in vivo astrocyte population identified by c-Fos activation in a mouse model of multiple sclerosis modulated by S1P signaling: immediate-early Astrocytes (ieAstrocytes). eNeuro 5

    Google Scholar 

  42. Shimizu T (2009) Lipid mediators in health and disease: enzymes and receptors as therapeutic targets for the regulation of immunity and inflammation. Annu Rev Pharmacol Toxicol 49:123–150

    Article  CAS  PubMed  Google Scholar 

  43. Kita Y, Ohto T, Uozumi N, Shimizu T (2006) Biochemical properties and pathophysiological roles of cytosolic phospholipase A2s. Biochim Biophys Acta 1761:1317–1322

    Article  CAS  PubMed  Google Scholar 

  44. Kalyvas A, David S (2004) Cytosolic phospholipase A2 plays a key role in the pathogenesis of multiple sclerosis-like disease. Neuron 41:323–335

    Article  CAS  PubMed  Google Scholar 

  45. Cunningham TJ, Yao L, Oetinger M, Cort L, Blankenhorn EP, Greenstein JI (2006) Secreted phospholipase A2 activity in experimental autoimmune encephalomyelitis and multiple sclerosis. J Neuroinflammation 3:26

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Uozumi N, Kume K, Nagase T, Nakatani N, Ishii S, Tashiro F, Komagata Y, Maki K, Ikuta K, Ouchi Y, Miyazaki J, Shimizu T (1997) Role of cytosolic phospholipase A2 in allergic response and parturition. Nature 390:618–622

    Article  CAS  PubMed  Google Scholar 

  47. Marusic S, Leach MW, Pelker JW, Azoitei ML, Uozumi N, Cui J, Shen MW, Declercq CM, Miyashiro JS, Carito BA, Thakker P, Simmons DL, Leonard JP, Shimizu T, Clark JD (2005) Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis. J Exp Med 202:841–851

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Kalyvas A, Baskakis C, Magrioti V, Constantinou-Kokotou V, Stephens D, Lopez-Vales R, Lu JQ, Yong VW, Dennis EA, Kokotos G, David S (2009) Differing roles for members of the phospholipase A2 superfamily in experimental autoimmune encephalomyelitis. Brain 132:1221–1235

    Article  PubMed  PubMed Central  Google Scholar 

  49. Marusic S, Thakker P, Pelker JW, Stedman NL, Lee KL, Mckew JC, Han L, Xu X, Wolf SF, Borey AJ, Cui J, Shen MW, Donahue F, Hassan-Zahraee M, Leach MW, Shimizu T, Clark JD (2008) Blockade of cytosolic phospholipase A2 alpha prevents experimental autoimmune encephalomyelitis and diminishes development of Th1 and Th17 responses. J Neuroimmunol 204:29–37

    Article  CAS  PubMed  Google Scholar 

  50. Thakker P, Marusic S, Stedman NL, Lee KL, Mckew JC, Wood A, Goldman SJ, Leach MW, Collins M, Kuchroo VK, Wolf SF, Clark JD, Hassan-Zahraee M (2011) Cytosolic phospholipase A2alpha blockade abrogates disease during the tissue-damage effector phase of experimental autoimmune encephalomyelitis by its action on APCs. J Immunol 187:1986–1997

    Article  CAS  PubMed  Google Scholar 

  51. Smith WL, Urade Y, Jakobsson PJ (2011) Enzymes of the cyclooxygenase pathways of prostanoid biosynthesis. Chem Rev 111:5821–5865

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Vane JR, Botting RM (2003) The mechanism of action of aspirin. Thromb Res 110:255–258

    Article  CAS  PubMed  Google Scholar 

  53. Vane JR (1971) Inhibition of prostaglandin synthesis as a mechanism of action for aspirin-like drugs. Nat New Biol 231:232–235

    Article  CAS  PubMed  Google Scholar 

  54. Kolb LC, Karlson AG, Sayre GP (1952) Prevention of experimental allergic encephalomyelitis by various agents. Trans Am Neurol Assoc 56:117–121

    CAS  PubMed  Google Scholar 

  55. Tsau S, Emerson MR, Lynch SG, Levine SM (2015) Aspirin and multiple sclerosis. BMC Med 13:153

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  56. Good RA, Campbell B, Good TA (1949) Prophylactic and therapeutic effect of para-aminobenzoic acid and sodium salicylate on experimental allergic encephalomyelitis. Proc Soc Exp Biol Med 72:341–347

    Article  CAS  PubMed  Google Scholar 

  57. Miller H, Newell DJ, Ridley A (1961) Multiple sclerosis. Trials of maintenance treatment with prednisolone and soluble aspirin. Lancet 1:127–129

    Article  CAS  PubMed  Google Scholar 

  58. Miller HG, Foster JB, Newell DJ, Barwick DD, Brewis RA (1963) Multiple sclerosis: therapeutic trials of chloroquine, soluble aspirin, and gammaglobulin. Br Med J 2:1436–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Miyamoto K, Miyake S, Mizuno M, Oka N, Kusunoki S, Yamamura T (2006) Selective COX-2 inhibitor celecoxib prevents experimental autoimmune encephalomyelitis through COX-2-independent pathway. Brain 129:1984–1992

    Article  PubMed  Google Scholar 

  60. Patrono C, Garcia Rodriguez LA, Landolfi R, Baigent C (2005) Low-dose aspirin for the prevention of atherothrombosis. N Engl J Med 353:2373–2383

    Article  CAS  PubMed  Google Scholar 

  61. Mondal S, Jana M, Dasarathi S, Roy A, Pahan K (2018) Aspirin ameliorates experimental autoimmune encephalomyelitis through interleukin-11-mediated protection of regulatory T cells. Sci Signal 11:eaar8278

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Kihara Y, Gupta S, Maurya MR, Armando A, Shah I, Quehenberger O, Glass CK, Dennis EA, Subramaniam S (2014a) Modeling of eicosanoid fluxes reveals functional coupling between cyclooxygenases and terminal synthases. Biophys J 106:966–975

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Murakami M, Kambe-Ohkura T, Kudo I (2002) Functional coupling between phospholipase A2S and cyclooxygenases in immediate and delayed prostanoid biosynthetic pathways. Adv Exp Med Biol 507:15–19

    Article  CAS  PubMed  Google Scholar 

  64. Ueno N, Takegoshi Y, Kamei D, Kudo I, Murakami M (2005) Coupling between cyclooxygenases and terminal prostanoid synthases. Biochem Biophys Res Commun 338:70–76

    Article  CAS  PubMed  Google Scholar 

  65. Takemiya T, Kawakami M, Takeuchi C (2018) Endothelial microsomal prostaglandin E Synthetase-1 Upregulates vascularity and endothelial interleukin-1beta in deteriorative progression of experimental autoimmune encephalomyelitis. Int J Mol Sci 19:3647

    Article  PubMed Central  CAS  Google Scholar 

  66. Takemiya T, Takeuchi C, Kawakami M (2017) Microsomal prostaglandin E Synthase-1 facilitates an intercellular interaction between CD4(+) T cells through IL-1beta Autocrine function in experimental autoimmune encephalomyelitis. Int J Mol Sci 18:2758

    Article  PubMed Central  CAS  Google Scholar 

  67. Takeuchi C, Matsumoto Y, Kohyama K, Uematsu S, Akira S, Yamagata K, Takemiya T (2013) Microsomal prostaglandin E synthase-1 aggravates inflammation and demyelination in a mouse model of multiple sclerosis. Neurochem Int 62:271–280

    Article  CAS  PubMed  Google Scholar 

  68. Esaki Y, Li Y, Sakata D, Yao C, Segi-Nishida E, Matsuoka T, Fukuda K, Narumiya S (2010) Dual roles of PGE2-EP4 signaling in mouse experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 107:12233–12238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Yao C, Sakata D, Esaki Y, Li Y, Matsuoka T, Kuroiwa K, Sugimoto Y, Narumiya S (2009) Prostaglandin E2-EP4 signaling promotes immune inflammation through Th1 cell differentiation and Th17 cell expansion. Nat Med 15:633–640

    Article  CAS  PubMed  Google Scholar 

  70. Zhou W, Dowell DR, Huckabee MM, Newcomb DC, Boswell MG, Goleniewska K, Lotz MT, Toki S, Yin H, Yao S, Natarajan C, Wu P, Sriram S, Breyer RM, Fitzgerald GA, Peebles RS Jr (2012) Prostaglandin I2 signaling drives Th17 differentiation and exacerbates experimental autoimmune encephalomyelitis. PLoS One 7:e33518

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Muramatsu R, Takahashi C, Miyake S, Fujimura H, Mochizuki H, Yamashita T (2012) Angiogenesis induced by CNS inflammation promotes neuronal remodeling through vessel-derived prostacyclin. Nat Med 18:1658–1664

    Article  CAS  PubMed  Google Scholar 

  72. Narumiya S, Ogorochi T, Nakao K, Hayaishi O (1982) Prostaglandin D2 in rat brain, spinal cord and pituitary: basal level and regional distribution. Life Sci 31:2093–2103

    Article  CAS  PubMed  Google Scholar 

  73. Huang YC, Lyu RK, Tseng MY, Chang HS, Hsu WC, Kuo HC, Chu CC, Wu YR, Ro LS, Huang CC, Chen CM (2009) Decreased intrathecal synthesis of prostaglandin D2 synthase in the cerebrospinal fluid of patients with acute inflammatory demyelinating polyneuropathy. J Neuroimmunol 206:100–105

    Article  CAS  PubMed  Google Scholar 

  74. Kagitani-Shimono K, Mohri I, Oda H, Ozono K, Suzuki K, Urade Y, Taniike M (2006) Lipocalin-type prostaglandin D synthase (beta-trace) is upregulated in the alphaB-crystallin-positive oligodendrocytes and astrocytes in the chronic multiple sclerosis. Neuropathol Appl Neurobiol 32:64–73

    Article  CAS  PubMed  Google Scholar 

  75. Cai W, Yang T, Liu H, Han L, Zhang K, Hu X, Zhang X, Yin KJ, Gao Y, Bennett MVL, Leak RK, Chen J (2018) Peroxisome proliferator-activated receptor gamma (PPARgamma): a master gatekeeper in CNS injury and repair. Prog Neurobiol 163–164:27–58

    Article  PubMed  CAS  Google Scholar 

  76. Natarajan C, Muthian G, Barak Y, Evans RM, Bright JJ (2003) Peroxisome proliferator-activated receptor-gamma-deficient heterozygous mice develop an exacerbated neural antigen-induced Th1 response and experimental allergic encephalomyelitis. J Immunol 171:5743–5750

    Article  PubMed  Google Scholar 

  77. Raikwar HP, Muthian G, Rajasingh J, Johnson C, Bright JJ (2005) PPARgamma antagonists exacerbate neural antigen-specific Th1 response and experimental allergic encephalomyelitis. J Neuroimmunol 167:99–107

    Article  CAS  PubMed  Google Scholar 

  78. Diab A, Deng C, Smith JD, Hussain RZ, Phanavanh B, Lovett-Racke AE, Drew PD, Racke MK (2002) Peroxisome proliferator-activated receptor-gamma agonist 15-deoxy-Delta(12,14)-prostaglandin J(2) ameliorates experimental autoimmune encephalomyelitis. J Immunol 168:2508–2515

    Article  CAS  PubMed  Google Scholar 

  79. Niino M, Iwabuchi K, Kikuchi S, Ato M, Morohashi T, Ogata A, Tashiro K, Onoe K (2001) Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-gamma. J Neuroimmunol 116:40–48

    Article  CAS  PubMed  Google Scholar 

  80. Radmark O, Werz O, Steinhilber D, Samuelsson B (2015) 5-Lipoxygenase, a key enzyme for leukotriene biosynthesis in health and disease. Biochim Biophys Acta 1851:331–339

    Article  PubMed  CAS  Google Scholar 

  81. Singh NK, Rao GN (2018) Emerging role of 12/15-Lipoxygenase (ALOX15) in human pathologies. Prog Lipid Res 73:28–45

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  82. Serhan CN (2017) Treating inflammation and infection in the 21st century: new hints from decoding resolution mediators and mechanisms. FASEB J 31:1273–1288

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Serhan CN, Chiang N, Dalli J (2018) New pro-resolving n-3 mediators bridge resolution of infectious inflammation to tissue regeneration. Mol Asp Med 64:1–17

    Article  CAS  Google Scholar 

  84. Serhan CN, Levy BD (2018) Resolvins in inflammation: emergence of the pro-resolving superfamily of mediators. J Clin Invest 128:2657–2669

    Article  PubMed  PubMed Central  Google Scholar 

  85. Whitney LW, Ludwin SK, Mcfarland HF, Biddison WE (2001) Microarray analysis of gene expression in multiple sclerosis and EAE identifies 5-lipoxygenase as a component of inflammatory lesions. J Neuroimmunol 121:40–48

    Article  CAS  PubMed  Google Scholar 

  86. Emerson MR, Levine SM (2004) Experimental allergic encephalomyelitis is exacerbated in mice deficient for 12/15-lipoxygenase or 5-lipoxygenase. Brain Res 1021:140–145

    Article  CAS  PubMed  Google Scholar 

  87. Yokomizo T, Nakamura M, Shimizu T (2018) Leukotriene receptors as potential therapeutic targets. J Clin Invest 128:2691–2701

    Article  PubMed  PubMed Central  Google Scholar 

  88. Kanaoka Y, Boyce JA (2014) Cysteinyl leukotrienes and their receptors; emerging concepts. Allergy Asthma Immunol Res 6:288–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. NationalMSSociety.org (2018) National Multiple Sclerosis Society [Online]. Available: https://www.nationalmssociety.org/. Accessed 2018

  90. Gladue RP, Carroll LA, Milici AJ, Scampoli DN, Stukenbrok HA, Pettipher ER, Salter ED, Contillo L, Showell HJ (1996) Inhibition of leukotriene B4-receptor interaction suppresses eosinophil infiltration and disease pathology in a murine model of experimental allergic encephalomyelitis. J Exp Med 183:1893–1898

    Article  CAS  PubMed  Google Scholar 

  91. Honda Z, Ishii S, Shimizu T (2002) Platelet-activating factor receptor. J Biochem 131:773–779

    Article  CAS  PubMed  Google Scholar 

  92. Honda Z, Nakamura M, Miki I, Minami M, Watanabe T, Seyama Y, Okado H, Toh H, Ito K, Miyamoto T, Et AL (1991) Cloning by functional expression of platelet-activating factor receptor from guinea-pig lung. Nature 349:342–346

    Article  CAS  PubMed  Google Scholar 

  93. Shindou H, Shimizu T (2009) Acyl-CoA:lysophospholipid acyltransferases. J Biol Chem 284:1–5

    Article  CAS  PubMed  Google Scholar 

  94. Kono N, Arai H (2019) Platelet-activating factor acetylhydrolases: an overview and update. Biochim Biophys Acta Mol Cell Biol Lipids 1864(6):922–931

    Article  CAS  PubMed  Google Scholar 

  95. Brochet B, Guinot P, Orgogozo JM, Confavreux C, Rumbach L, Lavergne V (1995) Double blind placebo controlled multicentre study of ginkgolide B in treatment of acute exacerbations of multiple sclerosis. The Ginkgolide Study Group in multiple sclerosis. J Neurol Neurosurg Psychiatry 58:360–362

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Callea L, Arese M, Orlandini A, Bargnani C, Priori A, Bussolino F (1999) Platelet activating factor is elevated in cerebral spinal fluid and plasma of patients with relapsing-remitting multiple sclerosis. J Neuroimmunol 94:212–221

    Article  CAS  PubMed  Google Scholar 

  97. Lock C, Hermans G, Pedotti R, Brendolan A, Schadt E, Garren H, Langer-Gould A, Strober S, Cannella B, Allard J, Klonowski P, Austin A, Lad N, Kaminski N, Galli SJ, Oksenberg JR, Raine CS, Heller R, Steinman L (2002) Gene-microarray analysis of multiple sclerosis lesions yields new targets validated in autoimmune encephalomyelitis. Nat Med 8:500–508

    Article  CAS  PubMed  Google Scholar 

  98. Osoegawa M, Miyagishi R, Ochi H, Nakamura I, Niino M, Kikuchi S, Murai H, Fukazawa T, Minohara M, Tashiro K, Kira J (2005) Platelet-activating factor receptor gene polymorphism in Japanese patients with multiple sclerosis. J Neuroimmunol 161:195–198

    Article  CAS  PubMed  Google Scholar 

  99. Bellizzi MJ, Geathers JS, Allan KC, Gelbard HA (2016) Platelet-activating factor receptors mediate excitatory postsynaptic hippocampal injury in experimental autoimmune Encephalomyelitis. J Neurosci 36:1336–1346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Rodrigues DH, Lacerda-Queiroz N, De Miranda AS, Fagundes CT, Campos RD, Arantes RE, Vilela Mde C, Rachid MA, Teixeira MM, Teixeira AL (2011) Absence of PAF receptor alters cellular infiltrate but not rolling and adhesion of leukocytes in experimental autoimmune encephalomyelitis. Brain Res 1385:298–306

    Article  CAS  PubMed  Google Scholar 

  101. Kihara Y, Maceyka M, Spiegel S, Chun J (2014b) Lysophospholipid receptor nomenclature review: IUPHAR review 8. Br J Pharmacol 171:3575–3594

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Fahy E, Sud M, Cotter D, Subramaniam S (2007) LIPID MAPS online tools for lipid research. Nucleic Acids Res 35:W606–W612

    Article  PubMed  PubMed Central  Google Scholar 

  103. Alexander SP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Buneman OP, Cidlowski JA, Christopoulos A, Davenport AP, Fabbro D, Spedding M, Striessnig J, Davies JA, Collaborators C (2017) The concise guide to pharmacology 2017/18: overview. Br J Pharmacol 174(Suppl 1):S1–S16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Shindou H, Hishikawa D, Harayama T, Yuki K, Shimizu T (2009) Recent progress on acyl CoA: lysophospholipid acyltransferase research. J Lipid Res 50(Suppl):S46–S51

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Aikawa S, Hashimoto T, Kano K, Aoki J (2015) Lysophosphatidic acid as a lipid mediator with multiple biological actions. J Biochem 157:81–89

    Article  CAS  PubMed  Google Scholar 

  106. Nishimasu H, Ishitani R, Aoki J, Nureki O (2012) A 3D view of autotaxin. Trends Pharmacol Sci 33:138–145

    Article  CAS  PubMed  Google Scholar 

  107. Aoki J, Nagai Y, Hosono H, Inoue K, Arai H (2002) Structure and function of phosphatidylserine-specific phospholipase A1. Biochim Biophys Acta 1582:26–32

    Article  CAS  PubMed  Google Scholar 

  108. Kihara Y, Mizuno H, Chun J (2015b) Lysophospholipid receptors in drug discovery. Exp Cell Res 333:171–177

    Article  CAS  PubMed  Google Scholar 

  109. Sheng X, Yung YC, Chen A, Chun J (2015) Lysophosphatidic acid signalling in development. Development 142:1390–1395

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Yung YC, Stoddard NC, Chun J (2014) LPA receptor signaling: pharmacology, physiology, and pathophysiology. J Lipid Res 55:1192–1214

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Yung YC, Stoddard NC, Mirendil H, Chun J (2015) Lysophosphatidic acid signaling in the nervous system. Neuron 85:669–682

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Mizuno H, Kihara Y, Kussrow A, Chen A, Ray M, Rivera R, Bornhop D, Chun J (2018) Lysophospholipid G protein-coupled receptor binding parameters as determined by backscattering interferometry (BSI). J Lipid Res 60:212–217

    Article  PubMed  PubMed Central  Google Scholar 

  113. Tokumura A, Fukuzawa K, Akamatsu Y, Yamada S, Suzuki T, Tsukatani H (1978) Identification of vasopressor phospholipid in crude soybean lecithin. Lipids 13:468–472

    Article  CAS  PubMed  Google Scholar 

  114. Schmitz K, Brunkhorst R, De Bruin N, Mayer CA, Haussler A, Ferreiros N, Schiffmann S, Parnham MJ, Tunaru S, Chun J, Offermanns S, Foerch C, Scholich K, Vogt J, Wicker S, Lotsch J, Geisslinger G, Tegeder I (2017) Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis. Acta Neuropathol Commun 5:42

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Pollinger B, Krishnamoorthy G, Berer K, Lassmann H, Bosl MR, Dunn R, Domingues HS, Holz A, Kurschus FC, Wekerle H (2009) Spontaneous relapsing-remitting EAE in the SJL/J mouse: MOG-reactive transgenic T cells recruit endogenous MOG-specific B cells. J Exp Med 206:1303–1316

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  116. Balood M, Zahednasab H, Siroos B, Mesbah-Namin SA, Torbati S, Harirchian MH (2014) Elevated serum levels of lysophosphatidic acid in patients with multiple sclerosis. Hum Immunol 75:411–413

    Article  CAS  PubMed  Google Scholar 

  117. Jiang D, Ju W, Wu X, Zhan X (2018) Elevated lysophosphatidic acid levels in the serum and cerebrospinal fluid in patients with multiple sclerosis: therapeutic response and clinical implication. Neurol Res 40:335–339

    Article  CAS  PubMed  Google Scholar 

  118. Zahednasab H, Balood M, Harirchian MH, Mesbah-Namin SA, Rahimian N, Siroos B (2014) Increased autotaxin activity in multiple sclerosis. J Neuroimmunol 273:120–123

    Article  CAS  PubMed  Google Scholar 

  119. Fujiwara Y (2008) Cyclic phosphatidic acid - a unique bioactive phospholipid. Biochim Biophys Acta 1781:519–524

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yamamoto S, Yamashina K, Ishikawa M, Gotoh M, Yagishita S, Iwasa K, Maruyama K, Murakami-Murofushi K, Yoshikawa K (2017) Protective and therapeutic role of 2-carba-cyclic phosphatidic acid in demyelinating disease. J Neuroinflammation 14:142

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Maceyka M, Harikumar KB, Milstien S, Spiegel S (2012) Sphingosine-1-phosphate signaling and its role in disease. Trends Cell Biol 22:50–60

    Article  CAS  PubMed  Google Scholar 

  122. Proia RL, Hla T (2015) Emerging biology of sphingosine-1-phosphate: its role in pathogenesis and therapy. J Clin Invest 125:1379–1387

    Article  PubMed  PubMed Central  Google Scholar 

  123. Chiba K (2005) FTY720, a new class of immunomodulator, inhibits lymphocyte egress from secondary lymphoid tissues and thymus by agonistic activity at sphingosine 1-phosphate receptors. Pharmacol Ther 108:308–319

    Article  CAS  PubMed  Google Scholar 

  124. Chiba K, Adachi K (2012) Discovery of fingolimod, the sphingosine 1-phosphate receptor modulator and its application for the therapy of multiple sclerosis. Future Med Chem 4:771–781

    Article  CAS  PubMed  Google Scholar 

  125. Chiba K, Hoshino Y, Suzuki C, Masubuchi Y, Yanagawa Y, Ohtsuki M, Sasaki S, Fujita T (1996) FTY720, a novel immunosuppressant possessing unique mechanisms. I. Prolongation of skin allograft survival and synergistic effect in combination with cyclosporine in rats. Transplant Proc 28:1056–1059

    CAS  PubMed  Google Scholar 

  126. Mansoor M, Melendez AJ (2008) Recent trials for FTY720 (fingolimod): a new generation of immunomodulators structurally similar to sphingosine. Rev Recent Clin Trials 3:62–69

    Article  CAS  PubMed  Google Scholar 

  127. Brinkmann V, Davis MD, Heise CE, Albert R, Cottens S, Hof R, Bruns C, Prieschl E, Baumruker T, Hiestand P, Foster CA, Zollinger M, Lynch KR (2002) The immune modulator FTY720 targets sphingosine 1-phosphate receptors. J Biol Chem 277:21453–21457

    Article  CAS  PubMed  Google Scholar 

  128. Mandala S, Hajdu R, Bergstrom J, Quackenbush E, Xie J, Milligan J, Thornton R, Shei GJ, Card D, Keohane C, Rosenbach M, Hale J, Lynch CL, Rupprecht K, Parsons W, Rosen H (2002) Alteration of lymphocyte trafficking by sphingosine-1-phosphate receptor agonists. Science 296:346–349

    Article  CAS  PubMed  Google Scholar 

  129. Paugh SW, Payne SG, Barbour SE, Milstien S, Spiegel S (2003) The immunosuppressant FTY720 is phosphorylated by sphingosine kinase type 2. FEBS Lett 554:189–193

    Article  CAS  PubMed  Google Scholar 

  130. Lo CG, Xu Y, Proia RL, Cyster JG (2005) Cyclical modulation of sphingosine-1-phosphate receptor 1 surface expression during lymphocyte recirculation and relationship to lymphoid organ transit. J Exp Med 201:291–301

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Matloubian M, Lo CG, Cinamon G, Lesneski MJ, Xu Y, Brinkmann V, Allende ML, Proia RL, Cyster JG (2004) Lymphocyte egress from thymus and peripheral lymphoid organs is dependent on S1P receptor 1. Nature 427:355–360

    Article  CAS  PubMed  Google Scholar 

  132. Pappu R, Schwab SR, Cornelissen I, Pereira JP, Regard JB, Xu Y, Camerer E, Zheng YW, Huang Y, Cyster JG, Coughlin SR (2007) Promotion of lymphocyte egress into blood and lymph by distinct sources of sphingosine-1-phosphate. Science 316:295–298

    Article  CAS  PubMed  Google Scholar 

  133. Schwab SR, Pereira JP, Matloubian M, Xu Y, Huang Y, Cyster JG (2005) Lymphocyte sequestration through S1P lyase inhibition and disruption of S1P gradients. Science 309:1735–1739

    Article  CAS  PubMed  Google Scholar 

  134. Garris CS, Wu L, Acharya S, Arac A, Blaho VA, Huang Y, Moon BS, Axtell RC, Ho PP, Steinberg GK, Lewis DB, Sobel RA, Han DK, Steinman L, Snyder MP, Hla T, Han MH (2013) Defective sphingosine 1-phosphate receptor 1 (S1P1) phosphorylation exacerbates TH17-mediated autoimmune neuroinflammation. Nat Immunol 14:1166–1172

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Thangada S, Khanna KM, Blaho VA, Oo ML, Im DS, Guo C, Lefrancois L, Hla T (2010) Cell-surface residence of sphingosine 1-phosphate receptor 1 on lymphocytes determines lymphocyte egress kinetics. J Exp Med 207:1475–1483

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Liu Y, Wada R, Yamashita T, Mi Y, Deng CX, Hobson JP, Rosenfeldt HM, Nava VE, Chae SS, Lee MJ, Liu CH, Hla T, Spiegel S, Proia RL (2000) Edg-1, the G protein-coupled receptor for sphingosine-1-phosphate, is essential for vascular maturation. J Clin Invest 106:951–961

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  137. Eken A, Duhen R, Singh AK, Fry M, Buckner JH, Kita M, Bettelli E, Oukka M (2017) S1P1 deletion differentially affects TH17 and Regulatory T cells. Sci Rep 7:12905

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  138. Blaho VA, Galvani S, Engelbrecht E, Liu C, Swendeman SL, Kono M, Proia RL, Steinman L, Han MH, Hla T (2015) HDL-bound sphingosine-1-phosphate restrains lymphopoiesis and neuroinflammation. Nature 523:342–346

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Foster CA, Howard LM, Schweitzer A, Persohn E, Hiestand PC, Balatoni B, Reuschel R, Beerli C, Schwartz M, Billich A (2007) Brain penetration of the oral immunomodulatory drug FTY720 and its phosphorylation in the central nervous system during experimental autoimmune encephalomyelitis: consequences for mode of action in multiple sclerosis. J Pharmacol Exp Ther 323:469–475

    Article  CAS  PubMed  Google Scholar 

  140. Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K, Teo ST, Yung YC, Lu M, Kennedy G, Chun J (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci U S A 108:751–756

    Article  CAS  PubMed  Google Scholar 

  141. Kappos L, Bar-Or A, Cree BAC, Fox RJ, Giovannoni G, Gold R, Vermersch P, Arnold DL, Arnould S, Scherz T, Wolf C, Wallstrom E, Dahlke F, Investigators EC (2018) Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, phase 3 study. Lancet 391:1263–1273

    Article  CAS  PubMed  Google Scholar 

  142. Cruz-Orengo L, Daniels BP, Dorsey D, Basak SA, Grajales-Reyes JG, Mccandless EE, Piccio L, Schmidt RE, Cross AH, Crosby SD, Klein RS (2014) Enhanced sphingosine-1-phosphate receptor 2 expression underlies female CNS autoimmunity susceptibility. J Clin Invest 124:2571–2584

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Seyedsadr MS, Weinmann O, Amorim A, Ineichen BV, Egger M, Mirnajafi-Zadeh J, Becher B, Javan M, Schwab ME (2018) Inactivation of sphingosine-1-phosphate receptor 2 (S1PR2) decreases demyelination and enhances remyelination in animal models of multiple sclerosis. Neurobiol Dis 124:189–201

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

Thanks to Prof. Takao Shimizu and all the members in his laboratory (The University of Tokyo), and Prof. Takehiko Yokomizo (Juntendo University) and Prof. Satoshi Ishii (Akita University) for their support to complete my Ph.D. work, Profs. K. Frank Austen and Yoshihide Kanaoka (Harvard University) for providing me an opportunity to study in the U.S.A., Profs. Edward A. Dennis and Shankar Subramaniam for acceptance to join LIPID MAPS®, Prof. Jerold Chun (Sanford Burnham Prebys Medical Discovery Institute (SBP)) for his continuous support and encouragement, Dr. Deepa Jonnalagadda (SBP) for helpful discussions, and Ms. Danielle Jones (SBP) for editorial assistance. This work was supported by a grant from NIH/NINDS R01NS103940 and fellowships from Japan Society for the Promotion of Science and Human Frontier Science Program.

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Y.K. declares no competing financial interests.

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    Yasuyuki Kihara

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    Kenneth V. Honn

  2. National Institutes of Health, Durham, NC, USA

    Darryl C. Zeldin

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Kihara, Y. (2019). Systematic Understanding of Bioactive Lipids in Neuro-Immune Interactions: Lessons from an Animal Model of Multiple Sclerosis. In: Honn, K., Zeldin, D. (eds) The Role of Bioactive Lipids in Cancer, Inflammation and Related Diseases. Advances in Experimental Medicine and Biology, vol 1161. Springer, Cham. https://doi.org/10.1007/978-3-030-21735-8_13

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