Untargeted plasma metabolomics identifies endogenous metabolite with drug-like properties in chronic animal model of multiple sclerosis

Journal of Biological Chemistry

Volumn 290, Issue 52, 2015, Pages 30697-30712

  Poisson, Laila M ^a,b   Suhail, Hamid ^c   Singh, Jaspreet ^c   Datta, Indrani ^a,b   Deni, Aleksandar ^b,c   Labuzek, Krzysztof ^d   Hoda, Nasrul ^e,f   Shankar, Ashray ^c   Kumar, Ashok ^g   Cerghet, Mirela ^c   Elias, Stanton ^c   Mohney, Robert P ^h   Rodriguez, Moses ^d   Rattan, Ramandeep ^i,j   Mangalam, Ashutosh K ^k   Giri, Shailendra ^c,l  

^a Center for Bioinformatics   (India)

^b Departments of Public Health Sciences   (India)

^c Department of Neurology ^*  (India)

^d MEDICAL UNIVERSITY OF SILESIA   (Poland)

^e MEDICAL COLLEGE OF GEORGIA   (United States)

^f UNIVERSITY OF GEORGIA   (United States)

^g WAYNE STATE UNIVERSITY SCHOOL OF MEDICINE   (United States)

^h METABOLON INC   (United States)

ⁱ UNIVERSITY OF IOWA   (United States)

^j MAYO GRADUATE SCHOOL   (United States)

^k HENRY FORD HEALTH SYSTEM   (United States)

^l HENRY FORD HOSPITAL   (United States)

more..

Author keywords

[No Author keywords available]

Indexed keywords

BIOINFORMATICS; BIOMOLECULES; FATTY ACIDS; LINOLEIC ACID; MAMMALS; METABOLISM;

BIOINFORMATICS ANALYSIS; DISEASE PROGRESSION; ENDOGENOUS METABOLITES; FALSE DISCOVERY RATE; MITOCHONDRIAL FUNCTION; MONOCYTES/MACROPHAGES; ORAL ADMINISTRATION; PROOF OF PRINCIPLES;

METABOLITES;

ANTIINFLAMMATORY AGENT; ARACHIDONIC ACID; ARGINASE 1; B7 ANTIGEN; CD86 ANTIGEN; CELL PROTEIN; FIZZ1 PROTEIN; GAMMA INTERFERON; GLUTAMIC ACID; GLUTAMINE; INDUCIBLE NITRIC OXIDE SYNTHASE; INTERLEUKIN 10; INTERLEUKIN 17; INTERLEUKIN 1BETA; INTERLEUKIN 23P19; INTERLEUKIN 5; INTERLEUKIN 6; LINOLEIC ACID; LINOLENIC ACID; MAJOR HISTOCOMPATIBILITY ANTIGEN CLASS 2; OMEGA 3 FATTY ACID; OMEGA 6 FATTY ACID; PENTOSE; RESOLVIN D1; RETINOID RELATED ORPHAN RECEPTOR GAMMA; TRANSCRIPTION FACTOR T BET; TRYPTOPHAN; TUMOR NECROSIS FACTOR ALPHA; UNCLASSIFIED DRUG; YM1 PROTEIN; UNSATURATED FATTY ACID;

AMINO ACID METABOLISM; ANIMAL CELL; ANIMAL EXPERIMENT; ANIMAL MODEL; ANIMAL TISSUE; ARTICLE; BIOINFORMATICS; CD4+ T LYMPHOCYTE; CELL INFILTRATION; CONTROLLED STUDY; CYTOKINE PRODUCTION; DISEASE COURSE; DOWN REGULATION; DRUG BLOOD LEVEL; DRUG EFFICACY; EXPERIMENTAL ALLERGIC ENCEPHALITIS; FATTY ACID SYNTHESIS; FEMALE; GENE EXPRESSION REGULATION; IFN GAMMA GENE; IL17 GENE; IL23P19 GENE; IL6 GENE; IMMUNOMODULATION; LYMPH NODE CELL; MACROPHAGE; METABOLITE; METABOLOMICS; MICROGLIA; MOG GENE; MONOCYTE; MOUSE; MULTIPLE SCLEROSIS; NONHUMAN; PLP GENE; POLARIZATION; PRIORITY JOURNAL; PROTEIN EXPRESSION; REGULATORY T LYMPHOCYTE; SIGNAL TRANSDUCTION; TH1 CELL; TH17 CELL; TH2 CELL; ANIMAL; CHEMISTRY; DISEASE MODEL; EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS; HUMAN; METABOLISM; PLASMA;

ANIMALS; DISEASE MODELS, ANIMAL; ENCEPHALOMYELITIS, AUTOIMMUNE, EXPERIMENTAL; FATTY ACIDS, UNSATURATED; FEMALE; HUMANS; METABOLIC NETWORKS AND PATHWAYS; METABOLOMICS; MICE; MULTIPLE SCLEROSIS; PLASMA;

EID: 84951763648     PISSN: 00219258     EISSN: 1083351X     Source Type: Journal    
DOI: 10.1074/jbc.M115.679068     Document Type: Article

References (89)

1. Miller, J. R. (2004) The importance of early diagnosis of multiple sclerosis. J. Manag. Care Pharm. 10, S4-S11
2. Lourenço, A. S., Baldeiras, I., Grãos, M., and Duarte, C. B. (2011) Proteomics-based technologies in the discovery of biomarkers for multiple sclerosis in the cerebrospinal fluid. Curr. Mol. Med. 11, 326-349
3. Zhang, A., Sun, H., Yan, G., Wang, P., and Wang, X. (2015) Metabolomics for biomarker discovery: Moving to the clinic. BioMed Res. Int. 2015, 354671
4. Nicholson, J. K., and Lindon, J. C. (2008) Systems biology: Metabonomics. Nature 455, 1054-1056
5. Zhang, A. H., Sun, H., and Wang, X. J. (2013) Recent advances in metabolomics in neurological disease, and future perspectives. Anal. Bioanal. Chem. 405, 8143-8150
6. Johnson, C. H., and Gonzalez, F. J. (2012) Challenges and opportunities of metabolomics. J. Cell Physiol. 227, 2975-2981
7. Mamas, M., Dunn, W. B., Neyses, L., and Goodacre, R. (2011) The role of metabolites and metabolomics in clinically applicable biomarkers of disease. Arch. Toxicol. 85, 5-17
8. Sato, Y., Suzuki, I., Nakamura, T., Bernier, F., Aoshima, K., and Oda, Y. (2012) Identification of a new plasma biomarker of Alzheimer's disease using metabolomics technology. J. Lipid Res. 53, 567-576
9. Trushina, E., Nemutlu, E., Zhang, S., Christensen, T., Camp, J., Mesa, J., Siddiqui, A., Tamura, Y., Sesaki, H., Wengenack, T. M., Dzeja, P. P., and Poduslo, J. F. (2012) Defects in mitochondrial dynamics and metabolomic signatures of evolving energetic stress in mouse models of familial Alzheimer's disease. PLoS One 7, e32737
10. Johansen, K. K., Wang, L., Aasly, J. O., White, L. R., Matson, W. R., Henchcliffe, C., Beal, M. F., and Bogdanov, M. (2009) Metabolomic profiling in LRRK2-related Parkinson's disease. PLoS One 4, e7551
11. Lutz, N. W., Fernandez, C., Pellissier, J. F., Cozzone, P. J., and Béraud, E. (2013) Cerebral biochemical pathways in experimental autoimmune encephalomyelitis and adjuvant arthritis: A comparative metabolomic study. PLoS One 8, e56101
12. Gebregiworgis, T., Massilamany, C., Gangaplara, A., Thulasingam, S., Kolli, V., Werth, M. T., Dodds, E. D., Steffen, D., Reddy, J., and Powers, R. (2013) Potential of urinary metabolites for diagnosing multiple sclerosis. ACS Chem. Biol. 8, 684-690
13. Noga, M. J., Dane, A., Shi, S., Attali, A., van Aken, H., Suidgeest, E., Tuinstra, T., Muilwijk, B., Coulier, L., Luider, T., Reijmers, T. H., Vreeken, R. J., and Hankemeier, T. (2012) Metabolomics of cerebrospinal fluid reveals changes in the central nervous system metabolism in a rat model of multiple sclerosis. Metabolomics 8, 253-263
14. Mangalam, A., Poisson, L., Nemutlu, E., Datta, I., Denic, A., Dzeja, P., Rodriguez, M., Rattan, R., and Giri, S. (2013) Profile of circulatory metabolites in a relapsing-remitting animal model of multiple sclerosis using global metabolomics. J. Clin. Cell Immunol. 4, 150
15. Holman, R. T., Johnson, S. B., and Kokmen, E. (1989) Deficiencies of polyunsaturated fatty acids and replacement by nonessential fatty acids in plasma lipids in multiple sclerosis. Proc. Natl. Acad. Sci. U.S.A. 86, 4720-4724
16. Gul, S., Smith, A. D., Thompson, R. H., Wright, H. P., and Zilkha, K. J. (1970) Fatty acid composition of phospholipids from platelets and erythrocytes in multiple sclerosis. J. Neurol. Neurosurg. Psychiatry 33, 506-510
17. Aupperle, R. L., Denney, D. R., Lynch, S. G., Carlson, S. E., and Sullivan, D. K. (2008) ω-3 fatty acids and multiple sclerosis: Relationship to depression. J. Behav. Med. 31, 127-135
18. Nightingale, S., Woo, E., Smith, A. D., French, J. M., Gale, M. M., Sinclair, H. M., Bates, D., and Shaw, D. A. (1990) Red blood cell and adipose tissue fatty acids in mild inactive multiple sclerosis. Acta Neurol. Scand. 82, 43-50
19. Cunnane, S. C., Ho, S. Y., Dore-Duffy, P., Ells, K. R., and Horrobin, D. F. (1989) Essential fatty acid and lipid profiles in plasma and erythrocytes in patients with multiple sclerosis. Am. J. Clin. Nutr. 50, 801-806
20. Serhan, C. N., Hong, S., Gronert, K., Colgan, S. P., Devchand, P. R., Mirick, G., and Moussignac, R. L. (2002) Resolvins: A family of bioactive products ofω-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammation signals. J. Exp. Med. 196, 1025-1037
21. Nath, N., Khan, M., Paintlia, M. K., Singh, I., Hoda, M. N., and Giri, S. (2009) Metformin attenuated the autoimmune disease of the central nervous system in animal models of multiple sclerosis. J. Immunol. 182, 8005-8014
22. Boudonck, K. J., Mitchell, M. W., Német, L., Keresztes, L., Nyska, A., Shinar, D., and Rosenstock, M. (2009) Discovery of metabolomics biomarkers for early detection of nephrotoxicity. Toxicol. Pathol. 37, 280-292
23. Evans, A. M., DeHaven, C. D., Barrett, T., Mitchell, M., and Milgram, E. (2009) Integrated, nontargeted ultrahigh performance liquid chromatography/electrospray ionization tandem mass spectrometry platform for the identification and relative quantification of the small-molecule complement of biological systems. Anal. Chem. 81, 6656-6667
24. Lawton, K. A., Berger, A., Mitchell, M., Milgram, K. E., Evans, A. M., Guo, L., Hanson, R. W., Kalhan, S. C., Ryals, J. A., and Milburn, M. V. (2008) Analysis of the adult human plasma metabolome. Pharmacogenomics 9, 383-397
25. Sreekumar, A., Poisson, L. M., Rajendiran, T. M., Khan, A. P., Cao, Q., Yu, J., Laxman, B., Mehra, R., Lonigro, R. J., Li, Y., Nyati, M. K., Ahsan, A., Kalyana-Sundaram, S., Han, B., Cao, X., et al. (2009) Metabolomic profiles delineate potential role for sarcosine in prostate cancer progression. Nature 457, 910-914
26. Evans, A. M., Bridgewater, B. R., Liu, Q., Mitchell, M. W., Robinson, R. J., Dai, H., Stewart, S. J., DeHaven, C. D., and Miller, L. A. (2014) High resolution mass spectrometry improves data quantity and quality as compared to unit mass resolution mass spectrometry in high-throughput profiling metabolomics. Metabolomics 4, 132
27. Dehaven, C. D., Evans, A. M., Dai, H., and Lawton, K. A. (2010) Organization of GC/MS and LC/MS metabolomics data into chemical libraries. J. Cheminform. 2, 9
28. Aittokallio, T., and Schwikowski, B. (2006) Graph-based methods for analysing networks in cell biology. Brief. Bioinform. 7, 243-255
29. Nath, N., Khan, M., Rattan, R., Mangalam, A., Makkar, R. S., de Meester, C., Bertrand, L., Singh, I., Chen, Y., Viollet, B., and Giri, S. (2009) Loss of AMPK exacerbates experimental autoimmune encephalomyelitis disease severity. Biochem. Biophys. Res. Commun. 386, 16-20
30. Xia, J., Mandal, R., Sinelnikov, I. V., Broadhurst, D., and Wishart, D. S. (2012) Metaboanalyst 2.0-a comprehensive server for metabolomic data analysis. Nucleic Acids Res. 40, W127-W133
31. Xia, J., Psychogios, N., Young, N., and Wishart, D. S. (2009) Metaboanalyst: A web server for metabolomic data analysis and interpretation. Nucleic Acids Res. 37, W652-W660
32. Goeman, J. J., and Bühlmann, P. (2007) Analyzing gene expression data in terms of gene sets: Methodological issues. Bioinformatics 23, 980-987
33. Seki, H., Sasaki, T., Ueda, T., and Arita, M. (2010) Resolvins as regulators of the immune system. ScientificWorldJournal 10, 818-831
34. Spite, M., Summers, L., Porter, T. F., Srivastava, S., Bhatnagar, A., and Serhan, C. N. (2009) Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress. Br. J. Pharmacol. 158, 1062-1073
35. Bento, A. F., Claudino, R. F., Dutra, R. C., Marcon, R., and Calixto, J. B. (2011) ω-3 fatty acid-derived mediators 17(R)-hydroxy docosahexaenoic acid, aspirin-triggered resolvin D1 and resolvin D2 prevent experimental colitis in mice. J. Immunol. 187, 1957-1969
36. Chen, F., Fan, X. H., Wu, Y. P., Zhu, J. L., Wang, F., Bo, L. L., Li, J. B., Bao, R., and Deng, X. M. (2014) Resolvin D1 improves survival in experimental sepsis through reducing bacterial load and preventing excessive activation of inflammatory response. Eur. J. Clin. Microbiol. Infect. Dis. 33, 457-464
37. Lima-Garcia, J. F., Dutra, R. C., da Silva, K., Motta, E. M., Campos, M. M., and Calixto, J. B. (2011) The precursor of resolvin D series and aspirintriggered resolvin D1 display anti-hyperalgesic properties in adjuvantinduced arthritis in rats. Br. J. Pharmacol. 164, 278-293
38. Rogerio, A. P., Haworth, O., Croze, R., Oh, S. F., Uddin, M., Carlo, T., Pfeffer, M. A., Priluck, R., Serhan, C. N., and Levy, B. D. (2012) Resolvin D1 and aspirin-triggered resolvin D1 promote resolution of allergic airways responses. J. Immunol. 189, 1983-1991
39. Tang, H., Liu, Y., Yan, C., Petasis, N. A., Serhan, C. N., and Gao, H. (2014) Protective actions of aspirin-triggered (17R) resolvin D1 and its analogue, 17R-hydroxy-19-para-fluorophenoxy-resolvin D1 methyl ester, in C5adependent IgG immune complex-induced inflammation and lung injury. J. Immunol. 193, 3769-3778
40. Recchiuti, A., Codagnone, M., Pierdomenico, A. M., Rossi, C., Mari, V. C., Cianci, E., Simiele, F., Gatta, V., and Romano, M. (2014) Immunoresolving actions of oral resolvin D1 include selective regulation of the transcription machinery in resolution-phase mouse macrophages. FASEB J. 28, 3090-3102
41. Croasdell, A., Thatcher, T. H., Kottmann, R. M., Colas, R. A., Dalli, J., Serhan, C. N., Sime, P. J., and Phipps, R. P. (2015) Resolvins attenuate inflammation and promote resolution in cigarette smoke-exposed human macrophages. Am. J. Physiol. Lung Cell. Mol. Physiol. 10.1152/ajplung.00125.2015
42. Hsiao, H. M., Sapinoro, R. E., Thatcher, T. H., Croasdell, A., Levy, E. P., Fulton, R. A., Olsen, K. C., Pollock, S. J., Serhan, C. N., Phipps, R. P., and Sime, P. J. (2013) A novel anti-inflammatory and pro-resolving role for resolvin D1 in acute cigarette smoke-induced lung inflammation. PLoS One 8, e58258
43. Rius, B., Titos, E., Morán-Salvador, E., López-Vicario, C., García-Alonso, V., González-Périz, A., Arroyo, V., and Clària, J. (2014) Resolvin D1 primes the resolution process initiated by calorie restriction in obesity-induced steatohepatitis. FASEB J. 28, 836-848
44. Rossi, S., Di Filippo, C., Gesualdo, C., Potenza, N., Russo, A., Trotta, M. C., Zippo, M. V., Maisto, R., Ferraraccio, F., Simonelli, F., and D'Amico, M. (2015) Protection from endotoxic uveitis by intravitreal resolvin D1: Involvement of lymphocytes, miRNAs, ubiquitin-proteasome, and M1/M2 macrophages. Mediators Inflamm. 2015, 149381
45. Titos, E., Rius, B., González-Périz, A., López-Vicario, C., Morán-Salvador, E., Martínez-Clemente, M., Arroyo, V., and Clària, J. (2011) Resolvin D1 and its precursor docosahexaenoic acid promote resolution of adipose tissue inflammation by eliciting macrophage polarization toward an M2-like phenotype. J. Immunol. 187, 5408-5418
46. Parsa, R., Andresen, P., Gillett, A., Mia, S., Zhang, X. M., Mayans, S., Holmberg, D., and Harris, R. A. (2012) Adoptive transfer of immunomodulatory M2 macrophages prevents type 1 diabetes in NOD mice. Diabetes 61, 2881-2892
47. Verreck, F. A., de Boer, T., Langenberg, D. M., van der Zanden, L., and Ottenhoff, T. H. (2006) Phenotypic and functional profiling of human proinflammatory type-1 and anti-inflammatory type-2 macrophages in response to microbial antigens and IFN-γ-and CD40L-mediated costimulation. J. Leukocyte Biol. 79, 285-293
48. Schulze-Topphoff, U., Shetty, A., Varrin-Doyer, M., Molnarfi, N., Sagan, S. A., Sobel, R. A., Nelson, P. A., and Zamvil, S. S. (2012) Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity. PLoS One 7, e33797
49. Weber, M. S., Prod'homme, T., Youssef, S., Dunn, S. E., Rundle, C. D., Lee, L., Patarroyo, J. C., Stüve, O., Sobel, R. A., Steinman, L., and Zamvil, S. S. (2007) Type II monocytes modulate T cell-mediated central nervous system autoimmune disease. Nat. Med. 13, 935-943
50. Lin, L., Huang, Z., Gao, Y., Yan, X., Xing, J., and Hang, W. (2011) LC-MS based serum metabonomic analysis for renal cell carcinoma diagnosis, staging, and biomarker discovery. J. Proteome Res. 10, 1396-1405
51. Okajima, K., Inoue, M., and Morino, Y. (1985) Studies on the mechanism for renal elimination of N-acetylphenylalanine: Its pathophysiologic significance in phenylketonuria. J. Lab. Clin. Med. 105, 132-138
52. Gabrilovich, D. I., and Nagaraj, S. (2009) Myeloid-derived suppressor cells as regulators of the immune system. Nat. Rev. Immunol. 9, 162-174
53. Skripuletz, T., Manzel, A., Gropengiesser, K., Schäfer, N., Gudi, V., Singh, V., Salinas Tejedor, L., Jörg, S., Hammer, A., Voss, E., Vulinovic, F., Degen, D., Wolf, R., Lee, D. H., et al. (2015) Pivotal role of choline metabolites in remyelination. Brain 138, 398-413
54. Mayo, L., Trauger, S. A., Blain, M., Nadeau, M., Patel, B., Alvarez, J. I., Mascanfroni, I. D., Yeste, A., Kivisäkk, P., Kallas, K., Ellezam, B., Bakshi, R., Prat, A., Antel, J. P., Weiner, H. L., and Quintana, F. J. (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat. Med. 20, 1147-1156
55. Jahng, A., Maricic, I., Aguilera, C., Cardell, S., Halder, R. C., and Kumar, V. (2004) Prevention of autoimmunity by targeting a distinct, noninvariant CD1d-reactive T cell population reactive to sulfatide. J. Exp. Med. 199, 947-957
56. Ho, P. P., Kanter, J. L., Johnson, A. M., Srinagesh, H. K., Chang, E. J., Purdy, T. M., van Haren, K., Wikoff, W. R., Kind, T., Khademi, M., Matloff, L. Y., Narayana, S., Hur, E. M., Lindstrom, T. M., He, Z., et al. (2012) Identification of naturally occurring fatty acids of the myelin sheath that resolve neuroinflammation. Sci. Transl. Med. 4, 137ra173
57. Haghikia, A., Jörg, S., Duscha, A., Berg, J., Manzel, A., Waschbisch, A., Hammer, A., Lee, D. H., May, C., Wilck, N., Balogh, A., Ostermann, A. I., Schebb, N. H., Akkad, D. A., Grohme, D. A., et al. (2015) Dietary fatty acids directly impact central nervous system autoimmunity via the small intestine. Immunity 43, 817-829
58. Campbell, B. M., Charych, E., Lee, A. W., and Möller, T. (2014) Kynurenines in CNS disease: Regulation by inflammatory cytokines. Front. Neurosci. 8, 12
59. Stone, T. W., and Darlington, L. G. (2013) The kynurenine pathway as a therapeutic target in cognitive and neurodegenerative disorders. Br. J. Pharmacol. 169, 1211-1227
60. Serhan, C. N., Chiang, N., and Dalli, J. (2015) The resolution code of acute inflammation: Novel pro-resolving lipid mediators in resolution. Semin. Immunol. 27, 200-215
61. Serhan, C. N. (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92-101
62. Buckley, C. D., Gilroy, D. W., and Serhan, C. N. (2014) Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40, 315-327
63. Spite, M., Clària, J., and Serhan, C. N. (2014) Resolvins, specialized proresolving lipid mediators, and their potential roles in metabolic diseases. Cell Metab. 19, 21-36
64. De Caterina, R. (2011) n-3 fatty acids in cardiovascular disease. N. Engl. J. Med. 364, 2439-2450
65. Dalli, J., Colas, R. A., and Serhan, C. N. (2013) Novel n-3 immunoresolvents: Structures and actions. Sci. Rep. 3, 1940
66. Jelinek, G. A., Hadgkiss, E. J., Weiland, T. J., Pereira, N. G., Marck, C. H., and van der Meer, D. M. (2013) Association of fish consumption and ω3 supplementation with quality of life, disability and disease activity in an international cohort of people with multiple sclerosis. Int. J. Neurosci. 123, 792-800
67. Weinstock-Guttman, B., Baier, M., Park, Y., Feichter, J., Lee-Kwen, P., Gallagher, E., Venkatraman, J., Meksawan, K., Deinehert, S., Pendergast, D., Awad, A. B., Ramanathan, M., Munschauer, F., and Rudick, R. (2005) Low fat dietary intervention with ω-3 fatty acid supplementation in multiple sclerosis patients. Prostaglandins Leukot. Essent. Fatty Acids 73, 397-404
68. Nordvik, I., Myhr, K. M., Nyland, H., and Bjerve, K. S. (2000) Effect of dietary advice and n-3 supplementation in newly diagnosed patients with MS. Acta Neurol. Scand. 102, 143-149
69. Kong, W., Yen, J. H., and Ganea, D. (2011) Docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific Th1/Th17 differentiation and suppresses experimental autoimmune encephalomyelitis. Brain. Behav. Immun. 25, 872-882
70. Chen, S., Zhang, H., Pu, H., Wang, G., Li, W., Leak, R. K., Chen, J., Liou, A. K., and Hu, X. (2014) n-3 PUFA supplementation benefits microglial responses to myelin pathology. Sci. Rep. 4, 7458
71. Torkildsen, O., Wergeland, S., Bakke, S., Beiske, A. G., Bjerve, K. S., Hovdal, H., Midgard, R., Lilleås, F., Pedersen, T., Bjørnarå, B., Dalene, F., Kleveland, G., Schepel, J., Olsen, I. C., and Myhr, K. M. (2012) ω-3 fatty acid treatment in multiple sclerosis (OFAMS Study): A randomized, doubleblind, placebo-controlled trial. Arch. Neurol. 69, 1044-1051
72. Wang, X., Zhu, M., Hjorth, E., Cortés-Toro, V., Eyjolfsdottir, H., Graff, C., Nennesmo, I., Palmblad, J., Eriksdotter, M., Sambamurti, K., Fitzgerald, J. M., Serhan, C. N., Granholm, A. C., and Schultzberg, M. (2015) Resolution of inflammation is altered in Alzheimer's disease. Alzheimer's Dementia 11, 40-50
73. Lukiw, W. J., Cui, J. G., Marcheselli, V. L., Bodker, M., Botkjaer, A., Gotlinger, K., Serhan, C. N., and Bazan, N. G. (2005) A role for docosahexaenoic acid-derived neuroprotectin D1 in neural cell survival and Alzheimer disease. J. Clin. Invest. 115, 2774-2783
74. Koivisto, H., Grimm, M. O., Rothhaar, T. L., Berkecz, R., Lütjohann, D. D., Giniatullina, R., Takalo, M., Miettinen, P. O., Lahtinen, H. M., Giniatullin, R., Penke, B., Janáky, T., Broersen, L. M., Hartmann, T., and Tanila, H. (2014) Special lipid-based diets alleviate cognitive deficits in the APPswe/PS1dE9 transgenic mouse model of Alzheimer's disease independent of brain amyloid deposition. J. Nutr. Biochem. 25, 157-169
75. Fiala, M., Halder, R. C., Sagong, B., Ross, O., Sayre, J., Porter, V., and Bredesen, D. E. (2015) ω-3 supplementation increases amyloid-β phagocytosis and resolvin D1 in patients with minor cognitive impairment. FASEB J. 29, 2681-2689
76. Mizwicki, M. T., Liu, G., Fiala, M., Magpantay, L., Sayre, J., Siani, A., Mahanian, M., Weitzman, R., Hayden, E. Y., Rosenthal, M. J., Nemere, I., Ringman, J., and Teplow, D. B. (2013) 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
77. Wang, X., Hjorth, E., Vedin, I., Eriksdotter, M., Freund-Levi, Y., Wahlund, L. O., Cederholm, T., Palmblad, J., and Schultzberg, M. (2015) Effects of n-3 FA supplementation on the release of proresolving lipid mediators by blood mononuclear cells: The OmegAD study. J. Lipid Res. 56, 674-681
78. Li, L., Wu, Y., Wang, Y., Wu, J., Song, L., Xian, W., Yuan, S., Pei, L., and Shang, Y. (2014) Resolvin D1 promotes the interleukin-4-induced alternative activation in BV-2 microglial cells. J. Neuroinflammation 11, 72
79. David, S., and Kroner, A. (2011) Repertoire of microglial and macrophage responses after spinal cord injury. Nat. Rev. Neurosci. 12, 388-399
80. Murray, P. J., and Wynn, T. A. (2011) Protective and pathogenic functions of macrophage subsets. Nat. Rev. Immunol. 11, 723-737
81. Chiang, N., Fredman, G., Bäckhed, F., Oh, S. F., Vickery, T., Schmidt, B. A., and Serhan, C. N. (2012) Infection regulates pro-resolving mediators that lower antibiotic requirements. Nature 484, 524-528
82. Johnston, J., and So, T. Y. (2012) First-line disease-modifying therapies in paediatric multiple sclerosis: A comprehensive overview. Drugs 72, 1195-1211
83. Melzer, N., and Meuth, S. G. (2014) Disease-modifying therapy in multiple sclerosis and chronic inflammatory demyelinating polyradiculoneuropathy: Common and divergent current and future strategies. Clin. Exp. Immunol. 175, 359-372
84. Schulze-Topphoff, U., Shetty, A., Varrin-Doyer, M., Molnarfi, N., Sagan, S. A., Sobel, R. A., Nelson, P. A., and Zamvil, S. S. (2012) Laquinimod, a quinoline-3-carboxamide, induces type II myeloid cells that modulate central nervous system autoimmunity. PLoS ONE 7, e33797
85. Choi, J. W., Gardell, S. E., Herr, D. R., Rivera, R., Lee, C. W., Noguchi, K., Teo, S. T., Yung, Y. C., Lu, M., Kennedy, G., and 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
86. Schilling, S., Goelz, S., Linker, R., Luehder, F., and Gold, R. (2006) Fumaric acid esters are effective in chronic experimental autoimmune encephalomyelitis and suppress macrophage infiltration. Clin. Exp. Immunol. 145, 101-107
87. Zhu, B., Bando, Y., Xiao, S., Yang, K., Anderson, A. C., Kuchroo, V. K., and Khoury, S. J. (2007) CD11b+Ly-6C(hi) suppressive monocytes in experimental autoimmune encephalomyelitis. J. Immunol. 179, 5228-5237
88. Ochando, J. C., and Chen, S. H. (2012) Myeloid-derived suppressor cells in transplantation and cancer. Immunol. Res. 54, 275-285
89. Umemura, N., Saio, M., Suwa, T., Kitoh, Y., Bai, J., Nonaka, K., Ouyang, G. F., Okada, M., Balazs, M., Adany, R., Shibata, T., and Takami, T. (2008) Tumor-infiltrating myeloid-derived suppressor cells are pleiotropic-inflamed monocytes/macrophages that bear M1-and M2-type characteristics. J. Leukocyte Biol. 83, 1136-1144