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Sphingolipids in neuroinflammation: a potential target for diagnosis and therapy

  • Lee, Ju Youn (Alzheimer's Disease Research Institute, Kyungpook National University) ;
  • Jin, Hee Kyung (Alzheimer's Disease Research Institute, Kyungpook National University) ;
  • Bae, Jae-sung (Alzheimer's Disease Research Institute, Kyungpook National University)
  • Received : 2019.10.08
  • Published : 2020.01.31

Abstract

Sphingolipids are ubiquitous building blocks of eukaryotic cell membranes that function as signaling molecules for regulating a diverse range of cellular processes, including cell proliferation, growth, survival, immune-cell trafficking, vascular and epithelial integrity, and inflammation. Recently, several studies have highlighted the pivotal role of sphingolipids in neuroinflammatory regulation. Sphingolipids have multiple functions, including induction of the expression of various inflammatory mediators and regulation of neuroinflammation by directly effecting the cells of the central nervous system. Accumulating evidence points to sphingolipid engagement in neuroinflammatory disorders, including Alzheimer's and Parkinson's diseases. Abnormal sphingolipid alterations, which involves an increase in ceramide and a decrease in sphingosine kinase, are observed during neuroinflammatory disease. These trends are observed early during disease development, and thus highlight the potential of sphingolipids as a new therapeutic and diagnostic target for neuroinflammatory diseases.

Keywords

References

  1. Maceyka M and Spiegel S (2014) Sphingolipid metabolites in inflammatory disease. Nature 510, 58-67 https://doi.org/10.1038/nature13475
  2. Merrill AH Jr (2011) Sphingolipid and glycosphingolipid metabolic pathways in the era of sphingolipidomics. Chem Rev 111, 6387-6422 https://doi.org/10.1021/cr2002917
  3. Hannun YA and Obeid LM (2018) Sphingolipids and their metabolism in physiology and disease. Nat Rev Mol Cell Biol 19, 175-191 https://doi.org/10.1038/nrm.2017.107
  4. Nixon GF (2009) Sphingolipids in inflammation: pathological implications and potential therapeutic targets. Br J Pharmacol 158, 982-993 https://doi.org/10.1111/j.1476-5381.2009.00281.x
  5. Chitnis T and Weiner HL (2017) CNS inflammation and neurodegeneration. J Clin Invest 127, 3577-3587 https://doi.org/10.1172/JCI90609
  6. Brambilla R (2019) Neuroinflammation, the thread connecting neurological disease : Cluster: "Neuroinflammatory mechanisms in neurodegenerative disorders". Acta Neuropathol 137, 689-691 https://doi.org/10.1007/s00401-019-02009-9
  7. Schwartz M and Baruch K (2014) The resolution of neuroinflammation in neurodegeneration: leukocyte recruitment via the choroid plexus. EMBO J 33, 7-22 https://doi.org/10.1002/embj.201386609
  8. Norris GT and Kipnis J (2019) Immune cells and CNS physiology: Microglia and beyond. J Exp Med 216, 60-70 https://doi.org/10.1084/jem.20180199
  9. Arcuri C, Mecca C, Bianchi R, Giambanco I and Donato R (2017) The Pathophysiological Role of Microglia in Dynamic Surveillance, Phagocytosis and Structural Remodeling of the Developing CNS. Front Mol Neurosci 10, 191 https://doi.org/10.3389/fnmol.2017.00191
  10. Zhu M, Wang X, Hjorth E et al (2016) Pro-Resolving Lipid Mediators Improve Neuronal Survival and Increase $A{\beta}42$ Phagocytosis. Mol Neurobiol 53, 2733-2749 https://doi.org/10.1007/s12035-015-9544-0
  11. Kosicek M and Hecimovic S (2013) Phospholipids and Alzheimer's disease: alterations, mechanisms and potential biomarkers. Int J Mol Sci 14, 1310-1322 https://doi.org/10.3390/ijms14011310
  12. Assi E, Cazzato D, De Palma C, Perrotta C, Clementi E and Cervia D (2013) Sphingolipids and brain resident macrophages in neuroinflammation: an emerging aspect of nervous system pathology. Clin Dev Immunol 2013, 309302
  13. Liu Q and Zhang J (2014) Lipid metabolism in Alzheimer's disease. Neurosci Bull 30, 331-345 https://doi.org/10.1007/s12264-013-1410-3
  14. Yin F, Sancheti H, Patil I and Cadenas E (2016) Energy metabolism and inflammation in brain aging and Alzheimer's disease. Free Radic Biol Med 100, 108-122 https://doi.org/10.1016/j.freeradbiomed.2016.04.200
  15. Davies L, Fassbender K and Walter S (2013) Sphingolipids in neuroinflammation. Handb Exp Pharmacol 216, 421-430 https://doi.org/10.1007/978-3-7091-1511-4_21
  16. Mesa-Herrera F, Taoro-Gonzalez L, Valdes-Baizabal C, Diaz M and Marin R (2019) Lipid and Lipid Raft Alteration in Aging and Neurodegenerative Diseases: A Window for the Development of New Biomarkers. Int J Mol Sci 20, E3810
  17. Di Pardo A and Maglione V (2018) Sphingolipid Metabolism: A New Therapeutic Opportunity for Brain Degenerative Disorders. Front Neurosci 12, 249 https://doi.org/10.3389/fnins.2018.00249
  18. Szepesi Z, Manouchehrian O, Bachiller S and Deierborg T (2018) Bidirectional Microglia-Neuron Communication in Health and Disease. Front Cell Neurosci 12, 323 https://doi.org/10.3389/fncel.2018.00323
  19. Young MM, Kester M and Wang HG (2013) Sphingolipids: regulators of crosstalk between apoptosis and autophagy. J Lipid Res 54, 5-19 https://doi.org/10.1194/jlr.R031278
  20. Czubowicz K, Jesko H, Wencel P, Lukiw WJ and Strosznajder RP (2019) The Role of Ceramide and Sphingosine-1-Phosphate in Alzheimer's Disease and Other Neurodegenerative Disorders. Mol Neurobiol 56, 5436-5455 https://doi.org/10.1007/s12035-018-1448-3
  21. Jesko H, Stepien A, Lukiw WJ and Strosznajder RP (2019) The Cross-Talk Between Sphingolipids and Insulin-Like Growth Factor Signaling: Significance for Aging and Neurodegeneration. Mol Neurobiol 56, 3501-3521 https://doi.org/10.1007/s12035-018-1286-3
  22. Pahan K, Sheikh FG, Khan M, Namboodiri AM and Singh I (1998) Sphingomyelinase and ceramide stimulate the expression of inducible nitric-oxide synthase in rat primary astrocytes. J Biol Chem 273, 2591-2600 https://doi.org/10.1074/jbc.273.5.2591
  23. Liu L, Martin R and Chan C (2013) Palmitate-activated astrocytes via serine palmitoyltransferase increase BACE1 in primary neurons by sphingomyelinases. Neurobiol Aging 34, 540-550 https://doi.org/10.1016/j.neurobiolaging.2012.05.017
  24. de Wit NM, den Hoedt S, Martinez-Martinez P, Rozemuller AJ, Mulder MT and de Vries HE (2019) Astrocytic ceramide as possible indicator of neuroinflammation. J Neuroinflammation 16, 48 https://doi.org/10.1186/s12974-019-1436-1
  25. Jung JS, Shin KO, Lee YM et al (2013) Anti-inflammatory mechanism of exogenous C2 ceramide in lipopolysaccharide-stimulated microglia. Biochim Biophys Acta 1831, 1016-1026 https://doi.org/10.1016/j.bbalip.2013.01.020
  26. Fischer I, Alliod C, Martinier N, Newcombe J, Brana C and Pouly S (2011) Sphingosine kinase 1 and sphingosine 1-phosphate receptor 3 are functionally upregulated on astrocytes under pro-inflammatory conditions. PLoS One 6, e23905 https://doi.org/10.1371/journal.pone.0023905
  27. Grassi S, Mauri L, Prioni S et al (2019) Sphingosine 1-Phosphate Receptors and Metabolic Enzymes as Druggable Targets for Brain Diseases. Front Pharmacol 10, 807 https://doi.org/10.3389/fphar.2019.00807
  28. Karunakaran I and van Echten-Deckert G (2017) Sphingosine 1-phosphate - A double edged sword in the brain. Biochim Biophys Acta Biomembr 1859, 1573-1582 https://doi.org/10.1016/j.bbamem.2017.03.008
  29. Spiegel S and Milstien S (2011) The outs and the ins of sphingosine-1-phosphate in immunity. Nat Rev Immunol 11, 403-415 https://doi.org/10.1038/nri2974
  30. Wu YP, Mizugishi K, Bektas M, Sandhoff R and Proia RL (2008) Sphingosine kinase 1/S1P receptor signaling axis controls glial proliferation in mice with Sandhoff disease. Hum Mol Genet 17, 2257-2264 https://doi.org/10.1093/hmg/ddn126
  31. Rothhammer V and Quintana FJ (2015) Control of autoimmune CNS inflammation by astrocytes. Semin Immunopathol 37, 625-638 https://doi.org/10.1007/s00281-015-0515-3
  32. Chalfant CE and Spiegel S (2005) Sphingosine 1-phosphate and ceramide 1-phosphate: expanding roles in cell signaling. J Cell Sci 118, 4605-4612 https://doi.org/10.1242/jcs.02637
  33. Lee JY, Han SH, Park MH et al (2018) Neuronal SphK1 acetylates COX2 and contributes to pathogenesis in a model of Alzheimer's Disease. Nat Commun 9, 1479 https://doi.org/10.1038/s41467-018-03674-2
  34. Kalgutkar AS, Crews BC, Rowlinson SW, Garner C, Seibert K and Marnett LJ (1998) Aspirin-like molecules that covalently inactivate cyclooxygenase-2. Science 280, 1268-1270 https://doi.org/10.1126/science.280.5367.1268
  35. Muller N (2019) COX-2 Inhibitors, Aspirin, and Other Potential Anti-Inflammatory Treatments for Psychiatric Disorders. Front Psychiatry 10, 375 https://doi.org/10.3389/fpsyt.2019.00375
  36. Serhan CN (2014) Pro-resolving lipid mediators are leads for resolution physiology. Nature 510, 92-101 https://doi.org/10.1038/nature13479
  37. Buckley CD, Gilroy DW and Serhan CN (2014) Proresolving lipid mediators and mechanisms in the resolution of acute inflammation. Immunity 40, 315-327 https://doi.org/10.1016/j.immuni.2014.02.009
  38. Fullerton JN, O'Brien AJ and Gilroy DW (2014) Lipid mediators in immune dysfunction after severe inflammation. Trends Immunol 35, 12-21 https://doi.org/10.1016/j.it.2013.10.008
  39. Mencarelli C and Martinez-Martinez P (2013) Ceramide function in the brain: when a slight tilt is enough. Cell Mol Life Sci 70, 181-203 https://doi.org/10.1007/s00018-012-1038-x
  40. Graham WV, Bonito-Oliva A and Sakmar TP (2017) Update on Alzheimer's Disease Therapy and Prevention Strategies. Annu Rev Med 68, 413-430 https://doi.org/10.1146/annurev-med-042915-103753
  41. Cerquera-Jaramillo MA, Nava-Mesa MO, Gonzalez-Reyes RE, Tellez-Conti C and de-la-Torre A (2018) Visual Features in Alzheimer's Disease: From Basic Mechanisms to Clinical Overview. Neural Plast 2018, 2941783 https://doi.org/10.1155/2018/2941783
  42. Heppner FL, Ransohoff RM and Becher B (2015) Immune attack: the role of inflammation in Alzheimer disease. Nat Rev Neurosci 16, 358-372 https://doi.org/10.1038/nrn3880
  43. Visan I (2017) Alzheimer's disease microglia. Nat Immunol 18, 876
  44. Katsumoto A, Takeuchi H, Takahashi K and Tanaka F (2018) Microglia in Alzheimer's Disease: Risk Factors and Inflammation. Front Neurol 9, 978 https://doi.org/10.3389/fneur.2018.00978
  45. Jazvinscak Jembrek M, Hof PR and Simic G (2015) Ceramides in Alzheimer's Disease: Key Mediators of Neuronal Apoptosis Induced by Oxidative Stress and $A{\beta}$ Accumulation. Oxid Med Cell Longev 2015, 346783 https://doi.org/10.1155/2015/346783
  46. Couttas TA, Kain N, Daniels B et al (2014) Loss of the neuroprotective factor Sphingosine 1-phosphate early in Alzheimer's disease pathogenesis. Acta Neuropathol Commun 2, 9 https://doi.org/10.1186/2051-5960-2-9
  47. Ceccom J, Loukh N, Lauwers-Cances V et al (2014) Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease. Acta Neuropathol Commun 2, 12 https://doi.org/10.1186/2051-5960-2-12
  48. Salter MW and Stevens B (2017) Microglia emerge as central players in brain disease. Nat Med 23, 1018-1027 https://doi.org/10.1038/nm.4397
  49. Ulland TK and Colonna M (2018) TREM2- a key player in microglial biology and Alzheimer disease. Nat Rev Neurol 14, 667-675 https://doi.org/10.1038/s41582-018-0072-1
  50. Fakhoury M (2018) Microglia and Astrocytes in Alzheimer's Disease: Implications for Therapy. Curr Neuropharmacol 16, 508-518 https://doi.org/10.2174/1570159X15666170720095240
  51. Kim SH, Noh MY, Kim HJ et al (2019) A Therapeutic Strategy for Alzheimer's Disease Focused on Immuneinflammatory Modulation. Dement Neurocogn Disord 18, 33-46 https://doi.org/10.12779/dnd.2019.18.2.33
  52. Alhouayek M and Muccioli GG (2014) COX-2-derived endocannabinoid metabolites as novel inflammatory mediators. Trends Pharmacol Sci 35, 284-292 https://doi.org/10.1016/j.tips.2014.03.001
  53. Bertolini A, Ottani A and Sandrini M (2002) Selective COX-2 inhibitors and dual acting anti-inflammatory drugs: critical remarks. Curr Med Chem 9, 1033-1043 https://doi.org/10.2174/0929867024606650
  54. Chiang N and Serhan CN (2004) Aspirin triggers formation of anti-inflammatory mediators: New mechanism for an old drug. Discov Med 4, 470-475
  55. Kotilinek LA, Westerman MA, Wang Q et al (2008) Cyclooxygenase-2 inhibition improves amyloid-betamediated suppression of memory and synaptic plasticity. Brain 131, 651-664 https://doi.org/10.1093/brain/awn008
  56. Mitchell JA and Warner TD (2006) COX isoforms in the cardiovascular system: understanding the activities of non-steroidal anti-inflammatory drugs. Nat Rev Drug Discov 5, 75-86 https://doi.org/10.1038/nrd1929
  57. Xu XM, Sansores-Garcia L, Chen XM, Matijevic-Aleksic N, Du M and Wu KK (1999) Suppression of inducible cyclooxygenase 2 gene transcription by aspirin and sodium salicylate. Proc Natl Acad Sci U S A 96, 5292-5297 https://doi.org/10.1073/pnas.96.9.5292
  58. Cuello AC (2017) Early and Late CNS Inflammation in Alzheimer's Disease: Two Extremes of a Continuum? Trends Pharmacol Sci 38, 956-966 https://doi.org/10.1016/j.tips.2017.07.005
  59. Poewe W, Seppi K, Tanner CM et al (2017) Parkinson disease. Nat Rev Dis Primers 3, 17013 https://doi.org/10.1038/nrdp.2017.13
  60. Engelender S and Isacson O (2017) The Threshold Theory for Parkinson's Disease. Trends Neurosci 40, 4-14 https://doi.org/10.1016/j.tins.2016.10.008
  61. Charvin D, Medori R, Hauser RA and Rascol O (2018) Therapeutic strategies for Parkinson disease: beyond dopaminergic drugs. Nat Rev Drug Discov 17, 844 https://doi.org/10.1038/nrd.2018.184
  62. McGregor MM and Nelson AB (2019) Circuit Mechanisms of Parkinson's Disease. Neuron 101, 1042-1056 https://doi.org/10.1016/j.neuron.2019.03.004