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Open Access 01-12-2019 | Original Paper

Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure

Authors: Marta Lombardi, Roberta Parolisi, Federica Scaroni, Elisabetta Bonfanti, Alice Gualerzi, Martina Gabrielli, Nicole Kerlero de Rosbo, Antonio Uccelli, Paola Giussani, Paola Viani, Cecilia Garlanda, Maria P. Abbracchio, Linda Chaabane, Annalisa Buffo, Marta Fumagalli, Claudia Verderio

Published in: Acta Neuropathologica | Issue 6/2019

Abstract

Microglia are highly plastic immune cells which exist in a continuum of activation states. By shaping the function of oligodendrocyte precursor cells (OPCs), the brain cells which differentiate to myelin-forming cells, microglia participate in both myelin injury and remyelination during multiple sclerosis. However, the mode(s) of action of microglia in supporting or inhibiting myelin repair is still largely unclear. Here, we analysed the effects of extracellular vesicles (EVs) produced in vitro by either pro-inflammatory or pro-regenerative microglia on OPCs at demyelinated lesions caused by lysolecithin injection in the mouse corpus callosum. Immunolabelling for myelin proteins and electron microscopy showed that EVs released by pro-inflammatory microglia blocked remyelination, whereas EVs produced by microglia co-cultured with immunosuppressive mesenchymal stem cells promoted OPC recruitment and myelin repair. The molecular mechanisms responsible for the harmful and beneficial EV actions were dissected in primary OPC cultures. By exposing OPCs, cultured either alone or with astrocytes, to inflammatory EVs, we observed a blockade of OPC maturation only in the presence of astrocytes, implicating these cells in remyelination failure. Biochemical fractionation revealed that astrocytes may be converted into harmful cells by the inflammatory EV cargo, as indicated by immunohistochemical and qPCR analyses, whereas surface lipid components of EVs promote OPC migration and/or differentiation, linking EV lipids to myelin repair. Although the mechanisms through which the lipid species enhance OPC maturation still remain to be fully defined, we provide the first demonstration that vesicular sphingosine 1 phosphate stimulates OPC migration, the first fundamental step in myelin repair. From this study, microglial EVs emerge as multimodal and multitarget signalling mediators able to influence both OPCs and astrocytes around myelin lesions, which may be exploited to develop novel approaches for myelin repair not only in multiple sclerosis, but also in neurological and neuropsychiatric diseases characterized by demyelination.

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Antonucci F, Turola E, Riganti L, Caleo M, Gabrielli M, Perrotta C et al (2012) Microvesicles released from microglia stimulate synaptic activity via enhanced sphingolipid metabolism. EMBO J 31:1231–1240. https://doi.org/10.1038/emboj.2011.489 CrossRefPubMedPubMedCentral

Arab T, Raffo-Romero A, Van Camp C, Lemaire Q, Le Marrec-Croq F, Drago F et al (2019) Proteomic characterisation of leech microglia extracellular vesicles (EVs): comparison between differential ultracentrifugation and Optiprep density gradient isolation. J Extracell Vesicles 8:1603048. https://doi.org/10.1080/20013078.2019.1603048 CrossRefPubMedPubMedCentral

Baecher-Allan C, Kaskow BJ, Weiner HL (2018) Multiple sclerosis: mechanisms and immunotherapy. Neuron 97:742–768. https://doi.org/10.1016/j.neuron.2018.01.021 CrossRefPubMed

Barenholz Y, Gibbes D, Litman BJ, Goll J, Thompson TE, Carlson RD (1977) A simple method for the preparation of homogeneous phospholipid vesicles. Biochemistry 16:2806–2810CrossRefPubMed

Bertero A, Liska A, Pagani M, Parolisi R, Masferrer ME, Gritti M et al (2018) Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human. Brain J Neurol 141:2055–2065. https://doi.org/10.1093/brain/awy111 CrossRef

Bin JM, Harris SN, Kennedy TE (2016) The oligodendrocyte-specific antibody ‘CC1’ binds Quaking 7. J Neurochem 139:181–186. https://doi.org/10.1111/jnc.13745 CrossRefPubMed

Bisht K, Sharma K, Lacoste B, Tremblay ME (2016) Dark microglia: why are they dark? Commun Integr Biol 9:e1230575. https://doi.org/10.1080/19420889.2016.1230575 CrossRefPubMedPubMedCentral

Blakemore WF, Gilson JM, Crang AJ (2003) The presence of astrocytes in areas of demyelination influences remyelination following transplantation of oligodendrocyte progenitors. Exp Neurol 184:955–963. https://doi.org/10.1016/S0014-4886(03)00347-9 CrossRefPubMed

Boda E, Di Maria S, Rosa P, Taylor V, Abbracchio MP, Buffo A (2015) Early phenotypic asymmetry of sister oligodendrocyte progenitor cells after mitosis and its modulation by aging and extrinsic factors. Glia 63:271–286. https://doi.org/10.1002/glia.22750 CrossRefPubMed

10.

Bonavita E, Gentile S, Rubino M, Maina V, Papait R, Kunderfranco P et al (2015) PTX3 is an extrinsic oncosuppressor regulating complement-dependent inflammation in cancer. Cell 160:700–714. https://doi.org/10.1016/j.cell.2015.01.004 CrossRefPubMed

11.

Bonfanti E, Gelosa P, Fumagalli M, Dimou L, Vigano F, Tremoli E et al (2017) The role of oligodendrocyte precursor cells expressing the GPR17 receptor in brain remodeling after stroke. Cell Death Dis 8:e2871. https://doi.org/10.1038/cddis.2017.256 CrossRefPubMedPubMedCentral

12.

Brambilla R (2019) The contribution of astrocytes to the neuroinflammatory response in multiple sclerosis and experimental autoimmune encephalomyelitis. Acta Neuropathol 137:757–783. https://doi.org/10.1007/s00401-019-01980-7 CrossRefPubMedPubMedCentral

13.

Brambilla R, Ashbaugh JJ, Magliozzi R, Dellarole A, Karmally S, Szymkowski DE et al (2011) Inhibition of soluble tumour necrosis factor is therapeutic in experimental autoimmune encephalomyelitis and promotes axon preservation and remyelination. Brain J Neurol 134:2736–2754. https://doi.org/10.1093/brain/awr199 CrossRef

14.

Butovsky O, Landa G, Kunis G, Ziv Y, Avidan H, Greenberg N et al (2006) Induction and blockage of oligodendrogenesis by differently activated microglia in an animal model of multiple sclerosis. J Clin Invest 116:905–915. https://doi.org/10.1172/JCI26836 CrossRefPubMedPubMedCentral

15.

Casella G, Colombo F, Finardi A, Descamps H, Ill-Raga G, Spinelli A et al (2018) Extracellular vesicles containing IL-4 modulate neuroinflammation in a mouse model of multiple sclerosis. Mol Ther 26:2107–2118. https://doi.org/10.1016/j.ymthe.2018.06.024 CrossRefPubMedPubMedCentral

16.

Chan JR, Watkins TA, Cosgaya JM, Zhang C, Chen L, Reichardt LF et al (2004) NGF controls axonal receptivity to myelination by Schwann cells or oligodendrocytes. Neuron 43:183–191. https://doi.org/10.1016/j.neuron.2004.06.024 CrossRefPubMedPubMedCentral

17.

Chang C, Lang H, Geng N, Wang J, Li N, Wang X (2013) Exosomes of BV-2 cells induced by alpha-synuclein: important mediator of neurodegeneration in PD. Neurosci Lett 548:190–195. https://doi.org/10.1016/j.neulet.2013.06.009 CrossRefPubMed

18.

Cherry JD, Olschowka JA, O’Banion MK (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J Neuroinflamm 11:98. https://doi.org/10.1186/1742-2094-11-98 CrossRef

19.

Choi JW, Gardell SE, Herr DR, Rivera R, Lee CW, Noguchi K et al (2011) FTY720 (fingolimod) efficacy in an animal model of multiple sclerosis requires astrocyte sphingosine 1-phosphate receptor 1 (S1P1) modulation. Proc Natl Acad Sci USA 108:751–756. https://doi.org/10.1073/pnas.1014154108 CrossRefPubMed

20.

Clarke LE, Liddelow SA, Chakraborty C, Munch AE, Heiman M, Barres BA (2018) Normal aging induces A1-like astrocyte reactivity. Proc Natl Acad Sci USA 115:E1896–E1905. https://doi.org/10.1073/pnas.1800165115 CrossRefPubMedPubMedCentral

21.

Colombo E, Farina C (2016) Astrocytes: key regulators of neuroinflammation. Trends Immunol 37:608–620. https://doi.org/10.1016/j.it.2016.06.006 CrossRefPubMed

22.

Colombo F, Bastoni M, Nigro A, Podini P, Finardi A, Casella G et al (2018) Cytokines stimulate the release of microvesicles from myeloid cells independently from the P2X7 receptor/acid sphingomyelinase pathway. Front Immunol 9:204. https://doi.org/10.3389/fimmu.2018.00204 CrossRefPubMedPubMedCentral

23.

Cui QL, Fang J, Kennedy TE, Almazan G, Antel JP (2014) Role of p38MAPK in S1P receptor-mediated differentiation of human oligodendrocyte progenitors. Glia 62:1361–1375. https://doi.org/10.1002/glia.22688 CrossRefPubMed

24.

Domingues HS, Portugal CC, Socodato R, Relvas JB (2016) Oligodendrocyte, astrocyte, and microglia crosstalk in myelin development, damage, and repair. Front Cell Dev Biol 4:71. https://doi.org/10.3389/fcell.2016.00071 CrossRefPubMedPubMedCentral

25.

Drago F, Lombardi M, Prada I, Gabrielli M, Joshi P, Cojoc D et al (2017) ATP modifies the proteome of extracellular vesicles released by microglia and influences their action on astrocytes. Front Pharmacol 8:910. https://doi.org/10.3389/fphar.2017.00910 CrossRefPubMedPubMedCentral

26.

Dubochet J, Adrian M, Chang JJ, Homo JC, Lepault J, McDowall AW et al (1988) Cryo-electron microscopy of vitrified specimens. Q Rev Biophys 21:129–228CrossRefPubMed

27.

El Hajj H, Savage JC, Bisht K, Parent M, Vallieres L, Rivest S et al (2019) Ultrastructural evidence of microglial heterogeneity in Alzheimer’s disease amyloid pathology. J Neuroinflamm 16:87. https://doi.org/10.1186/s12974-019-1473-9 CrossRef

28.

Fischer MT, Wimmer I, Hoftberger R, Gerlach S, Haider L, Zrzavy T et al (2013) Disease-specific molecular events in cortical multiple sclerosis lesions. Brain J Neurol 136:1799–1815. https://doi.org/10.1093/brain/awt110 CrossRef

29.

Fitzgerald W, Freeman ML, Lederman MM, Vasilieva E, Romero R, Margolis L (2018) A system of cytokines encapsulated in extracellular vesicles. Sci Rep 8:8973. https://doi.org/10.1038/s41598-018-27190-x CrossRefPubMedPubMedCentral

30.

Franklin RJ, Goldman SA (2015) Glia disease and repair-remyelination. Csh Perspect Biol 7:a020594. https://doi.org/10.1101/cshperspect.a020594 CrossRef

31.

Fumagalli M, Bonfanti E, Daniele S, Zappelli E, Lecca D, Martini C et al (2015) The ubiquitin ligase Mdm2 controls oligodendrocyte maturation by intertwining mTOR with G protein-coupled receptor kinase 2 in the regulation of GPR17 receptor desensitization. Glia 63:2327–2339. https://doi.org/10.1002/glia.22896 CrossRefPubMed

32.

Fumagalli M, Daniele S, Lecca D, Lee PR, Parravicini C, Fields RD et al (2011) Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. J Biol Chem 286:10593–10604. https://doi.org/10.1074/jbc.M110.162867 CrossRefPubMedPubMedCentral

33.

Fumagalli M, Lecca D, Abbracchio MP (2016) CNS remyelination as a novel reparative approach to neurodegenerative diseases: the roles of purinergic signaling and the P2Y-like receptor GPR17. Neuropharmacol 104:82–93. https://doi.org/10.1016/j.neuropharm.2015.10.005 CrossRef

34.

Gabrielli M, Battista N, Riganti L, Prada I, Antonucci F, Cantone L et al (2015) Active endocannabinoids are secreted on extracellular membrane vesicles. EMBO Rep 16:213–220. https://doi.org/10.15252/embr.201439668 CrossRefPubMedPubMedCentral

35.

Ginhoux F, Greter M, Leboeuf M, Nandi S, See P, Gokhan S et al (2010) Fate mapping analysis reveals that adult microglia derive from primitive macrophages. Science 330:841–845. https://doi.org/10.1126/science.1194637 CrossRefPubMedPubMedCentral

36.

Giunti D, Parodi B, Usai C, Vergani L, Casazza S, Bruzzone S et al (2012) Mesenchymal stem cells shape microglia effector functions through the release of CX3CL1. Stem cells 30:2044–2053. https://doi.org/10.1002/stem.1174 CrossRefPubMed

37.

Goldmann T, Wieghofer P, Muller PF, Wolf Y, Varol D, Yona S et al (2013) A new type of microglia gene targeting shows TAK1 to be pivotal in CNS autoimmune inflammation. Nat Neurosci 16:1618–1626. https://doi.org/10.1038/nn.3531 CrossRefPubMed

38.

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. https://doi.org/10.1016/j.jns.2013.02.011 CrossRefPubMedPubMedCentral

39.

Gualerzi A, Kooijmans SAA, Niada S, Picciolini S, Brini AT, Camussi G et al (2019) Raman spectroscopy as a quick tool to assess purity of extracellular vesicle preparations and predict their functionality. J Extracell Vesicles 8:1568780. https://doi.org/10.1080/20013078.2019.1568780 CrossRefPubMedPubMedCentral

40.

Gualerzi A, Niada S, Giannasi C, Picciolini S, Morasso C, Vanna R et al (2017) Raman spectroscopy uncovers biochemical tissue-related features of extracellular vesicles from mesenchymal stromal cells. Sci Rep 7:9820. https://doi.org/10.1038/s41598-017-10448-1 CrossRefPubMedPubMedCentral

41.

Hall SM (1972) The effect of injections of lysophosphatidyl choline into white matter of the adult mouse spinal cord. J Cell Sci 10:535–546PubMed

42.

Hammond TR, Gadea A, Dupree J, Kerninon C, Nait-Oumesmar B, Aguirre A et al (2014) Astrocyte-derived endothelin-1 inhibits remyelination through notch activation. Neuron 81:588–602. https://doi.org/10.1016/j.neuron.2013.11.015 CrossRefPubMedPubMedCentral

43.

Harris LA, Baffy N (2017) Modulation of the gut microbiota: a focus on treatments for irritable bowel syndrome. Postgrad Med 129:872–888. https://doi.org/10.1080/00325481.2017.1383819 CrossRefPubMed

44.

Hinks GL, Franklin RJ (2000) Delayed changes in growth factor gene expression during slow remyelination in the CNS of aged rats. Mol Cell Neurosci 16:542–556. https://doi.org/10.1006/mcne.2000.0897 CrossRefPubMed

45.

Hooper C, Sainz-Fuertes R, Lynham S, Hye A, Killick R, Warley A et al (2012) Wnt3a induces exosome secretion from primary cultured rat microglia. BMC Neurosci 13:144. https://doi.org/10.1186/1471-2202-13-144 CrossRefPubMedPubMedCentral

46.

Kalakh S, Mouihate A (2017) Androstenediol reduces demyelination-induced axonopathy in the rat corpus callosum: impact on microglial polarization. Front Cell Neurosci 11:49. https://doi.org/10.3389/fncel.2017.00049 CrossRefPubMedPubMedCentral

47.

Kemanetzoglou E, Andreadou E (2017) CNS Demyelination with TNF-alpha Blockers. Curr Neurol Neurosci 17:36. https://doi.org/10.1007/s11910-017-0742-1 CrossRef

48.

Keough MB, Jensen SK, Yong VW (2015) Experimental demyelination and remyelination of murine spinal cord by focal injection of lysolecithin. JoVE. https://doi.org/10.3791/52679 CrossRefPubMedPubMedCentral

49.

Kimura A, Ohmori T, Kashiwakura Y, Ohkawa R, Madoiwa S, Mimuro J et al (2008) Antagonism of sphingosine 1-phosphate receptor-2 enhances migration of neural progenitor cells toward an area of brain. Stroke 39:3411–3417. https://doi.org/10.1161/STROKEAHA.108.514612 CrossRefPubMed

50.

Kotter MR, Setzu A, Sim FJ, Van Rooijen N, Franklin RJ (2001) Macrophage depletion impairs oligodendrocyte remyelination following lysolecithin-induced demyelination. Glia 35:204–212CrossRefPubMed

51.

Krafft C, Wilhelm K, Eremin A, Nestel S, von Bubnoff N, Schultze-Seemann W et al (2017) A specific spectral signature of serum and plasma-derived extracellular vesicles for cancer screening. Nanomed Nanotechnol 13:835–841. https://doi.org/10.1016/j.nano.2016.11.016 CrossRef

52.

Kriebel PW, Majumdar R, Jenkins LM, Senoo H, Wang W, Ammu S et al (2018) Extracellular vesicles direct migration by synthesizing and releasing chemotactic signals. J Cell Biol 217:2891–2910. https://doi.org/10.1083/jcb.201710170 CrossRefPubMedPubMedCentral

53.

Kucharova K, Stallcup WB (2017) Distinct NG2 proteoglycan-dependent roles of resident microglia and bone marrow-derived macrophages during myelin damage and repair. PLoS One 12:e0187530. https://doi.org/10.1371/journal.pone.0187530 CrossRefPubMedPubMedCentral

54.

Kuhlmann T, Miron V, Cui Q, Wegner C, Antel J, Bruck W (2008) Differentiation block of oligodendroglial progenitor cells as a cause for remyelination failure in chronic multiple sclerosis. Brain 131:1749–1758. https://doi.org/10.1093/brain/awn096 CrossRefPubMed

55.

Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541:481–487. https://doi.org/10.1038/nature21029 CrossRefPubMedPubMedCentral

56.

Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Methods 25:402–408. https://doi.org/10.1006/meth.2001.1262 CrossRefPubMed

57.

Locatelli G, Theodorou D, Kendirli A, Jordao MJC, Staszewski O, Phulphagar K et al (2018) Mononuclear phagocytes locally specify and adapt their phenotype in a multiple sclerosis model. Nat Neurosci 21:1196–1208. https://doi.org/10.1038/s41593-018-0212-3 CrossRefPubMed

58.

Lock C, Oksenberg J, Steinman L (1999) The role of TNFalpha and lymphotoxin in demyelinating disease. Ann Rheum Dis 58(Suppl 1):I121–I128CrossRefPubMedPubMedCentral

59.

Maimone D, Gregory S, Arnason BG, Reder AT (1991) Cytokine levels in the cerebrospinal fluid and serum of patients with multiple sclerosis. J Neuroimmunol 32:67–74CrossRefPubMed

60.

Mallucci G, Peruzzotti-Jametti L, Bernstock JD, Pluchino S (2015) The role of immune cells, glia and neurons in white and gray matter pathology in multiple sclerosis. Prog Neurobiol 127–128:1–22. https://doi.org/10.1016/j.pneurobio.2015.02.003 CrossRefPubMed

61.

Marrone MC, Morabito A, Giustizieri M, Chiurchiu V, Leuti A, Mattioli M et al (2017) TRPV1 channels are critical brain inflammation detectors and neuropathic pain biomarkers in mice. Nature Commun 8:15292. https://doi.org/10.1038/ncomms15292 CrossRef

62.

Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI et al (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20:1147–1156. https://doi.org/10.1038/nm.3681 CrossRefPubMedPubMedCentral

63.

Miron VE (2017) Microglia-driven regulation of oligodendrocyte lineage cells, myelination, and remyelination. J Leukoc Biol 101:1103–1108. https://doi.org/10.1189/jlb.3RI1116-494R CrossRefPubMed

64.

Miron VE, Boyd A, Zhao JW, Yuen TJ, Ruckh JM, Shadrach JL et al (2013) M2 microglia and macrophages drive oligodendrocyte differentiation during CNS remyelination. Nat Neurosci 16:1211–1218. https://doi.org/10.1038/nn.3469 CrossRefPubMedPubMedCentral

65.

Miron VE, Ludwin SK, Darlington PJ, Jarjour AA, Soliven B, Kennedy TE et al (2010) Fingolimod (FTY720) enhances remyelination following demyelination of organotypic cerebellar slices. Am J Pathol 176:2682–2694. https://doi.org/10.2353/ajpath.2010.091234 CrossRefPubMedPubMedCentral

66.

Mycko MP, Papoian R, Boschert U, Raine CS, Selmaj KW (2003) cDNA microarray analysis in multiple sclerosis lesions: detection of genes associated with disease activity. Brain 126:1048–1057CrossRefPubMed

67.

Nash B, Thomson CE, Linington C, Arthur AT, McClure JD, McBride MW et al (2011) Functional duality of astrocytes in myelination. J Neurosci 31:13028–13038. https://doi.org/10.1523/JNEUROSCI.1449-11.2011 CrossRefPubMedPubMedCentral

68.

Okabe M, Ikawa M, Kominami K, Nakanishi T, Nishimune Y (1997) ‘Green mice’ as a source of ubiquitous green cells. FEBS Lett 407:313–319CrossRefPubMed

69.

Olah M, Amor S, Brouwer N, Vinet J, Eggen B, Biber K et al (2012) Identification of a microglia phenotype supportive of remyelination. Glia 60:306–321. https://doi.org/10.1002/glia.21266 CrossRefPubMed

70.

Orlov I, Myasnikov AG, Andronov L, Natchiar SK, Khatter H, Beinsteiner B et al (2017) The integrative role of cryo electron microscopy in molecular and cellular structural biology. Biol Cell 109:81–93. https://doi.org/10.1111/boc.201600042 CrossRefPubMed

71.

Paolicelli RC, Bergamini G, Rajendran L (2018) Cell-to-cell communication by extracellular vesicles: focus on microglia. Neuroscience. https://doi.org/10.1016/j.neuroscience.2018.04.003 CrossRefPubMedPubMedCentral

72.

Peferoen L, Kipp M, van der Valk P, van Noort JM, Amor S (2014) Oligodendrocyte-microglia cross-talk in the central nervous system. Immunology 141:302–313. https://doi.org/10.1111/imm.12163 CrossRefPubMedPubMedCentral

73.

Prada I, Amin L, Furlan R, Legname G, Verderio C, Cojoc D (2016) A new approach to follow a single extracellular vesicle-cell interaction using optical tweezers. Biotechniques 60:35–41. https://doi.org/10.2144/000114371 CrossRefPubMed

74.

Prada I, Furlan R, Matteoli M, Verderio C (2013) Classical and unconventional pathways of vesicular release in microglia. Glia 61:1003–1017. https://doi.org/10.1002/glia.22497 CrossRefPubMed

75.

Prada I, Gabrielli M, Turola E, Iorio A, D’Arrigo G, Parolisi R et al (2018) Glia-to-neuron transfer of miRNAs via extracellular vesicles: a new mechanism underlying inflammation-induced synaptic alterations. Acta Neuropathol 135:529–550. https://doi.org/10.1007/s00401-017-1803-x CrossRefPubMedPubMedCentral

76.

Pusic AD, Kraig RP (2014) Youth and environmental enrichment generate serum exosomes containing miR-219 that promote CNS myelination. Glia 62:284–299. https://doi.org/10.1002/glia.22606 CrossRefPubMed

77.

Pusic KM, Pusic AD, Kraig RP (2016) Environmental enrichment stimulates immune cell secretion of exosomes that promote CNS myelination and may regulate inflammation. Cell Mol Neurobiol 36:313–325. https://doi.org/10.1007/s10571-015-0269-4 CrossRefPubMedPubMedCentral

78.

Quigley EMM (2017) Microbiota-brain-gut axis and neurodegenerative diseases. Curr Neurol Neurosci 17:94. https://doi.org/10.1007/s11910-017-0802-6 CrossRef

79.

Riboni L, Viani P, Bassi R, Giussani P, Tettamanti G (2000) Cultured granule cells and astrocytes from cerebellum differ in metabolizing sphingosine. J Neurochem 75:503–510CrossRefPubMed

80.

Riboni L, Viani P, Tettamanti G (2000) Estimating sphingolipid metabolism and trafficking in cultured cells using radiolabeled compounds. Method Enzymol 311:656–682CrossRef

81.

Rothhammer V, Kenison JE, Tjon E, Takenaka MC, de Lima KA, Borucki DM et al (2017) Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc Natl Acad Sci USA 114:2012–2017. https://doi.org/10.1073/pnas.1615413114 CrossRefPubMedPubMedCentral

82.

Ruckh JM, Zhao JW, Shadrach JL, van Wijngaarden P, Rao TN, Wagers AJ et al (2012) Rejuvenation of regeneration in the aging central nervous system. Cell Stem Cell 10:96–103. https://doi.org/10.1016/j.stem.2011.11.019 CrossRefPubMedPubMedCentral

83.

Shields S, Gilson J, Blakemore W, Franklin R (2000) Remyelination occurs as extensively but more slowly in old rats compared to young rats following fliotoxin-induced CNS demyelination. Glia 29:102CrossRefPubMed

84.

Sim FJ, Zhao C, Penderis J, Franklin RJ (2002) The age-related decrease in CNS remyelination efficiency is attributable to an impairment of both oligodendrocyte progenitor recruitment and differentiation. J Neurosci 22:2451–2459. https://doi.org/10.1523/JNEUROSCI.22-07-02451.2002 CrossRefPubMedPubMedCentral

85.

Smith ZJ, Lee C, Rojalin T, Carney RP, Hazari S, Knudson A et al (2015) Single exosome study reveals subpopulations distributed among cell lines with variability related to membrane content. J Extracell Vesicles 4:28533. https://doi.org/10.3402/jev.v4.28533 CrossRefPubMed

86.

Soni S, O’Dea KP, Tan YY, Cho K, Abe E, Romano R et al (2019) ATP redirects cytokine trafficking and promotes novel membrane TNF signaling via microvesicles. FASEB J. https://doi.org/10.1096/fj.201802386r CrossRefPubMedPubMedCentral

87.

Sun D, Yu Z, Fang X, Liu M, Pu Y, Shao Q et al (2017) LncRNA GAS5 inhibits microglial M2 polarization and exacerbates demyelination. EMBO Rep 18:1801–1816. https://doi.org/10.15252/embr.201643668 CrossRefPubMedPubMedCentral

88.

Tatischeff I, Larquet E, Falcon-Perez JM, Turpin PY, Kruglik SG (2012) Fast characterisation of cell-derived extracellular vesicles by nanoparticles tracking analysis, cryo-electron microscopy, and Raman tweezers microspectroscopy. J Extracell Vesicles. https://doi.org/10.3402/jev.v1i0.19179 CrossRefPubMedPubMedCentral

89.

Tremblay ME, Lowery RL, Majewska AK (2010) Microglial interactions with synapses are modulated by visual experience. PLoS Biol 8:e1000527. https://doi.org/10.1371/journal.pbio.1000527 CrossRefPubMedPubMedCentral

90.

Turola E, Furlan R, Bianco F, Matteoli M, Verderio C (2012) Microglial microvesicle secretion and intercellular signaling. Front Physiol 3:149. https://doi.org/10.3389/fphys.2012.00149 CrossRefPubMedPubMedCentral

91.

Valentin-Torres A, Savarin C, Hinton DR, Phares TW, Bergmann CC, Stohlman SA (2016) Sustained TNF production by central nervous system infiltrating macrophages promotes progressive autoimmune encephalomyelitis. J Neuroinflamm 13:46. https://doi.org/10.1186/s12974-016-0513-y CrossRef

92.

Valentine WJ, Kiss GN, Liu J, Shuyu E, Gotoh M, Murakami-Murofushi K, Pham TC et al (2010) (S)-FTY720-vinylphosphonate, an analogue of the immunosuppressive agent FTY720, is a pan-antagonist of sphingosine 1-phosphate GPCR signaling and inhibits autotaxin activity. Cell Signal 22:1543–1553. https://doi.org/10.1016/j.cellsig.2010.05.023 CrossRefPubMedPubMedCentral

93.

Van Oosten BW, Barkhof F, Scholten PE, von Blomberg BM, Ader HJ, Polman CH (1998) Increased production of tumor necrosis factor alpha, and not of interferon gamma, preceding disease activity in patients with multiple sclerosis. Arch Neurol 55:793–798CrossRefPubMed

94.

Verderio C, Gabrielli M, Giussani P (2018) Role of sphingolipids in the biogenesis and biological activity of extracellular vesicles. J Lipid Res 59:1325–1340. https://doi.org/10.1194/jlr.R083915 CrossRefPubMedPubMedCentral

95.

Verderio C, Muzio L, Turola E, Bergami A, Novellino L, Ruffini F et al (2012) Myeloid microvesicles are a marker and therapeutic target for neuroinflammation. Ann Neurol 72:610–624. https://doi.org/10.1002/ana.23627 CrossRefPubMed

96.

Viani P, Giussani P, Brioschi L, Bassi R, Anelli V, Tettamanti G et al (2003) Ceramide in nitric oxide inhibition of glioma cell growth. Evidence for the involvement of ceramide traffic. J Biol Chem 278:9592–9601. https://doi.org/10.1074/jbc.M207729200 CrossRefPubMed

97.

Voss EV, Skuljec J, Gudi V, Skripuletz T, Pul R, Trebst C et al (2012) Characterisation of microglia during de- and remyelination: can they create a repair promoting environment? Neurobiol Dis 45:519–528. https://doi.org/10.1016/j.nbd.2011.09.008 CrossRefPubMed

98.

Yang Y, Boza-Serrano A, Dunning CJR, Clausen BH, Lambertsen KL, Deierborg T (2018) Inflammation leads to distinct populations of extracellular vesicles from microglia. J Neuroinflamm 15:168. https://doi.org/10.1186/s12974-018-1204-7 CrossRef

99.

Yun SP, Kam TI, Panicker N, Kim S, Oh Y, Park JS et al (2018) Block of A1 astrocyte conversion by microglia is neuroprotective in models of Parkinson’s disease. Nat Med 24:931–938. https://doi.org/10.1038/s41591-018-0051-5 CrossRefPubMedPubMedCentral

100.

Zabala A, Vazquez-Villoldo N, Rissiek B, Gejo J, Martin A, Palomino A et al (2018) P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. EMBO Mol Med. https://doi.org/10.15252/emmm.201708743 CrossRefPubMedPubMedCentral

101.

Zanier ER, Pischiutta F, Riganti L, Marchesi F, Turola E, Fumagalli S et al (2014) Bone marrow mesenchymal stromal cells drive protective M2 microglia polarization after brain trauma. Neurotherapeutics 11:679–695. https://doi.org/10.1007/s13311-014-0277-y CrossRefPubMedPubMedCentral

102.

Zappia E, Casazza S, Pedemonte E, Benvenuto F, Bonanni I, Gerdoni E et al (2005) Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T-cell anergy. Blood 106:1755–1761. https://doi.org/10.1182/blood-2005-04-1496 CrossRefPubMed

Title: Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure
Authors: Marta Lombardi
Roberta Parolisi
Federica Scaroni
Elisabetta Bonfanti
Alice Gualerzi
Martina Gabrielli
Nicole Kerlero de Rosbo
Antonio Uccelli
Paola Giussani
Paola Viani
Cecilia Garlanda
Maria P. Abbracchio
Linda Chaabane
Annalisa Buffo
Marta Fumagalli
Claudia Verderio
Publication date: 01-12-2019
Publisher: Springer Berlin Heidelberg
Published in: Acta Neuropathologica / Issue 6/2019
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-019-02049-1

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Detrimental and protective action of microglial extracellular vesicles on myelin lesions: astrocyte involvement in remyelination failure

Abstract

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

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