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G-Protein-Coupled Receptor Gpr17 Expression in Two Multiple Sclerosis Remyelination Models

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Abstract

In multiple sclerosis patients, demyelination is prominent in both the white and gray matter. Chronic clinical deficits are known to result from acute or chronic injury to the myelin sheath and inadequate remyelination. The underlying molecular mechanisms of remyelination and its failure remain currently unclear. Recent studies have recognized G protein-coupled receptor 17 (GPR17) as an important regulator of oligodendrocyte development and remyelination. So far, the relevance of GPR17 for myelin repair was mainly tested in remyelinating white matter lesions. The relevance of GPR17 for gray matter remyelination as well as remyelination of chronic white matter lesions was not addressed so far. Here, we provide a detailed characterization of GPR17 expression during experimental de- and remyelination. Experimental lesions with robust and limited endogenous remyelination capacity were established by either acute or chronic cuprizone-induced demyelination. Furthermore, remyelinating lesions were induced by the focal injection of lysophosphatidylcholine (LPC) into the corpus callosum. GPR17 expression was analyzed by complementary techniques including immunohistochemistry, in situ hybridization, and real-time PCR. In control animals, GPR17+ cells were evenly distributed in the corpus callosum and cortex and displayed a highly ramified morphology. Virtually all GPR17+ cells also expressed the oligodendrocyte-specific transcription factor OLIG2. After acute cuprizone-induced demyelination, robust endogenous remyelination was evident in the white matter corpus callosum but not in the gray matter cortex. Endogenous callosal remyelination was paralleled by a robust induction of GPR17 expression which was absent in the gray matter cortex. Higher numbers of GPR17+ cells were as well observed after LPC-induced focal white matter demyelination. In contrast, densities of GPR17+ cells were comparable to control animals after chronic cuprizone-induced demyelination indicating quiescence of this cell population. Our findings demonstrate that GPR17 expression induction correlates with acute demyelination and sufficient endogenous remyelination. This strengthens the view that manipulation of this receptor might be a therapeutic opportunity to support endogenous remyelination.

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References

  1. Aboul-Enein F, Lassmann H (2005) Mitochondrial damage and histotoxic hypoxia: a pathway of tissue injury in inflammatory brain disease? Acta Neuropathol 109(1):49–55. https://doi.org/10.1007/s00401-004-0954-8

    Article  CAS  PubMed  Google Scholar 

  2. Smith KJ, Lassmann H (2002) The role of nitric oxide in multiple sclerosis. Lancet Neurol 1(4):232–241

    Article  CAS  Google Scholar 

  3. Funfschilling U, Supplie LM, Mahad D, Boretius S, Saab AS, Edgar J, Brinkmann BG, Kassmann CM et al (2012) Glycolytic oligodendrocytes maintain myelin and long-term axonal integrity. Nature 485(7399):517–521. https://doi.org/10.1038/nature11007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Edgar JM, McLaughlin M, Yool D, Zhang SC, Fowler JH, Montague P, Barrie JA, McCulloch MC et al (2004) Oligodendroglial modulation of fast axonal transport in a mouse model of hereditary spastic paraplegia. J Cell Biol 166(1):121–131. https://doi.org/10.1083/jcb.200312012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Uschkureit T, Sporkel O, Stracke J, Bussow H, Stoffel W (2000) Early onset of axonal degeneration in double (plp-/-mag-/-) and hypomyelinosis in triple (plp-/-mbp-/-mag-/-) mutant mice. J Neurosci 20(14):5225–5233

    Article  CAS  Google Scholar 

  6. Patrikios P, Stadelmann C, Kutzelnigg A, Rauschka H, Schmidbauer M, Laursen H, Sorensen PS, Bruck W et al (2006) Remyelination is extensive in a subset of multiple sclerosis patients. Brain J Neurol 129(Pt 12):3165–3172. https://doi.org/10.1093/brain/awl217

    Article  Google Scholar 

  7. Frischer JM, Weigand SD, Guo Y, Kale N, Parisi JE, Pirko I, Mandrekar J, Bramow S et al (2015) Clinical and pathological insights into the dynamic nature of the white matter multiple sclerosis plaque. Ann Neurol 78(5):710–721. https://doi.org/10.1002/ana.24497

    Article  PubMed  PubMed Central  Google Scholar 

  8. Xing YL, Roth PT, Stratton JA, Chuang BH, Danne J, Ellis SL, Ng SW, Kilpatrick TJ et al (2014) Adult neural precursor cells from the subventricular zone contribute significantly to oligodendrocyte regeneration and remyelination. J Neurosci 34(42):14128–14146. https://doi.org/10.1523/jneurosci.3491-13.2014

    Article  PubMed  PubMed Central  Google Scholar 

  9. 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 J Neurol 131(Pt 7):1749–1758. https://doi.org/10.1093/brain/awn096

    Article  CAS  Google Scholar 

  10. Strijbis EMM, Kooi EJ, van der Valk P, Geurts JJG (2017) Cortical remyelination is heterogeneous in multiple sclerosis. J Neuropathol Exp Neurol 76(5):390–401. https://doi.org/10.1093/jnen/nlx023

    Article  CAS  PubMed  Google Scholar 

  11. Gudi V, Moharregh-Khiabani D, Skripuletz T, Koutsoudaki PN, Kotsiari A, Skuljec J, Trebst C, Stangel M (2009) Regional differences between grey and white matter in cuprizone induced demyelination. Brain Res 1283:127–138. https://doi.org/10.1016/j.brainres.2009.06.005

    Article  CAS  PubMed  Google Scholar 

  12. Baxi EG, DeBruin J, Jin J, Strasburger HJ, Smith MD, Orthmann-Murphy JL, Schott JT, Fairchild AN et al (2017) Lineage tracing reveals dynamic changes in oligodendrocyte precursor cells following cuprizone-induced demyelination. Glia 65(12):2087–2098. https://doi.org/10.1002/glia.23229

    Article  PubMed  PubMed Central  Google Scholar 

  13. Ou Z, Sun Y, Lin L, You N, Liu X, Li H, Ma Y, Cao L et al (2016) Olig2-targeted G-protein-coupled receptor Gpr17 regulates oligodendrocyte survival in response to lysolecithin-induced demyelination. J Neurosci 36(41):10560–10573. https://doi.org/10.1523/jneurosci.0898-16.2016

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Simon K, Hennen S, Merten N, Blattermann S, Gillard M, Kostenis E, Gomeza J (2016) The orphan G protein-coupled receptor GPR17 negatively regulates oligodendrocyte differentiation via Galphai/o and its downstream effector molecules. J Biol Chem 291(2):705–718. https://doi.org/10.1074/jbc.M115.683953

    Article  CAS  PubMed  Google Scholar 

  15. Coppi E, Maraula G, Fumagalli M, Failli P, Cellai L, Bonfanti E, Mazzoni L, Coppini R et al (2013) UDP-glucose enhances outward K(+) currents necessary for cell differentiation and stimulates cell migration by activating the GPR17 receptor in oligodendrocyte precursors. Glia 61(7):1155–1171. https://doi.org/10.1002/glia.22506

    Article  PubMed  Google Scholar 

  16. Lecca D, Trincavelli ML, Gelosa P, Sironi L, Ciana P, Fumagalli M, Villa G, Verderio C et al (2008) The recently identified P2Y-like receptor GPR17 is a sensor of brain damage and a new target for brain repair. PLoS One 3(10):e3579. https://doi.org/10.1371/journal.pone.0003579

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Ciana P, Fumagalli M, Trincavelli ML, Verderio C, Rosa P, Lecca D, Ferrario S, Parravicini C et al (2006) The orphan receptor GPR17 identified as a new dual uracil nucleotides/cysteinyl-leukotrienes receptor. EMBO J 25(19):4615–4627. https://doi.org/10.1038/sj.emboj.7601341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ceruti S, Vigano F, Boda E, Ferrario S, Magni G, Boccazzi M, Rosa P, Buffo A et al (2011) Expression of the new P2Y-like receptor GPR17 during oligodendrocyte precursor cell maturation regulates sensitivity to ATP-induced death. Glia 59(3):363–378. https://doi.org/10.1002/glia.21107

    Article  PubMed  Google Scholar 

  19. Fumagalli M, Daniele S, Lecca D, Lee PR, Parravicini C, Fields RD, Rosa P, Antonucci F et al (2011) Phenotypic changes, signaling pathway, and functional correlates of GPR17-expressing neural precursor cells during oligodendrocyte differentiation. J Biol Chem 286(12):10593–10604. https://doi.org/10.1074/jbc.M110.162867

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chen Y, Wu H, Wang S, Koito H, Li J, Ye F, Hoang J, Escobar SS et al (2009) The oligodendrocyte-specific G protein-coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci 12(11):1398–1406. https://doi.org/10.1038/nn.2410

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Hennen S, Wang H, Peters L, Merten N, Simon K, Spinrath A, Blattermann S, Akkari R et al (2013) Decoding signaling and function of the orphan G protein-coupled receptor GPR17 with a small-molecule agonist. Sci Signal 6(298):ra93. https://doi.org/10.1126/scisignal.2004350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Daniele S, Trincavelli ML, Fumagalli M, Zappelli E, Lecca D, Bonfanti E, Campiglia P, Abbracchio MP et al (2014) Does GRK-beta arrestin machinery work as a “switch on” for GPR17-mediated activation of intracellular signaling pathways? Cell Signal 26(6):1310–1325. https://doi.org/10.1016/j.cellsig.2014.02.016

    Article  CAS  PubMed  Google Scholar 

  23. Kipp M (2016) Remyelination strategies in multiple sclerosis: a critical reflection. Expert Rev Neurother 16(1):1–3. https://doi.org/10.1586/14737175.2016.1116387

    Article  CAS  PubMed  Google Scholar 

  24. Kipp M, Clarner T, Dang J, Copray S, Beyer C (2009) The cuprizone animal model: new insights into an old story. Acta Neuropathol 118(6):723–736. https://doi.org/10.1007/s00401-009-0591-3

    Article  PubMed  Google Scholar 

  25. Huang JK, Jarjour AA, Oumesmar BN, Kerninon C, Williams A, Krezel W, Kagechika H, Bauer J et al (2011) Retinoid X receptor gamma signaling accelerates CNS remyelination. Nat Neurosci 14(1):45–53. https://doi.org/10.1038/nn.2702

    Article  CAS  PubMed  Google Scholar 

  26. Slowik A, Schmidt T, Beyer C, Amor S, Clarner T, Kipp M (2015) The sphingosine 1-phosphate receptor agonist FTY720 is neuroprotective after cuprizone-induced CNS demyelination. Br J Pharmacol 172(1):80–92. https://doi.org/10.1111/bph.12938

    Article  CAS  PubMed  Google Scholar 

  27. Paxinos G, Franklin KBJ (2001) Mouse brain in stereotaxic coordinates. 2nd ed edn. Academic, San Diego, Calif. ; London,

  28. Paxinos G, Watson C The rat brain in stereotaxic coordinates Elsevier Academic Press

  29. Ruther BJ, Scheld M, Dreymueller D, Clarner T, Kress E, Brandenburg LO (2017) Combination of cuprizone and experimental autoimmune encephalomyelitis to study inflammatory brain lesion formation and progression. 65 (12):1900–1913. doi:https://doi.org/10.1002/glia.23202

    Article  Google Scholar 

  30. Clarner T, Janssen K, Nellessen L, Stangel M, Skripuletz T, Krauspe B, Hess FM, Denecke B et al (2015) CXCL10 triggers early microglial activation in the cuprizone model. J Immunology (Baltimore, Md: 1950) 194(7):3400–3413. https://doi.org/10.4049/jimmunol.1401459

    Article  CAS  Google Scholar 

  31. Skripuletz T, Lindner M, Kotsiari A, Garde N, Fokuhl J, Linsmeier F, Trebst C, Stangel M (2008) Cortical demyelination is prominent in the murine cuprizone model and is strain-dependent. Am J Pathol 172(4):1053–1061. https://doi.org/10.2353/ajpath.2008.070850

    Article  PubMed  PubMed Central  Google Scholar 

  32. Hoflich KM, Beyer C, Clarner T, Schmitz C, Nyamoya S, Kipp M, Hochstrasser T (2016) Acute axonal damage in three different murine models of multiple sclerosis: a comparative approach. Brain Res 1650:125–133. https://doi.org/10.1016/j.brainres.2016.08.048

    Article  CAS  PubMed  Google Scholar 

  33. Sahel A, Ortiz FC, Kerninon C, Maldonado PP, Angulo MC, Nait-Oumesmar B (2015) Alteration of synaptic connectivity of oligodendrocyte precursor cells following demyelination. Front Cell Neurosci 9:77. https://doi.org/10.3389/fncel.2015.00077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Vigano F, Schneider S, Cimino M, Bonfanti E, Gelosa P, Sironi L, Abbracchio MP, Dimou L (2016) GPR17 expressing NG2-glia: oligodendrocyte progenitors serving as a reserve pool after injury. Glia 64(2):287–299. https://doi.org/10.1002/glia.22929

    Article  PubMed  Google Scholar 

  35. Boda E, Vigano F, Rosa P, Fumagalli M, Labat-Gest V, Tempia F, Abbracchio MP, Dimou L et al (2011) The GPR17 receptor in NG2 expressing cells: focus on in vivo cell maturation and participation in acute trauma and chronic damage. Glia 59(12):1958–1973. https://doi.org/10.1002/glia.21237

    Article  PubMed  Google Scholar 

  36. Boccazzi M, Lecca D, Marangon D, Guagnini F, Abbracchio MP, Ceruti S (2016) A new role for the P2Y-like GPR17 receptor in the modulation of multipotency of oligodendrocyte precursor cells in vitro. Purinergic Signal 12(4):661–672

    Article  CAS  Google Scholar 

  37. Morrison H, Young K, Qureshi M, Rowe RK, Lifshitz J (2017) Quantitative microglia analyses reveal diverse morphologic responses in the rat cortex after diffuse brain injury. Sci Rep 7(1):13211. https://doi.org/10.1038/s41598-017-13581-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Nimmerjahn A, Kirchhoff F, Helmchen F (2005) Resting microglial cells are highly dynamic surveillants of brain parenchyma in vivo. Science 308(5726):1314–1318. https://doi.org/10.1126/science.1110647

    Article  CAS  PubMed  Google Scholar 

  39. Koutsoudaki PN, Hildebrandt H, Gudi V, Skripuletz T, Skuljec J, Stangel M (2010) Remyelination after cuprizone induced demyelination is accelerated in mice deficient in the polysialic acid synthesizing enzyme St8siaIV. Neuroscience 171(1):235–244. https://doi.org/10.1016/j.neuroscience.2010.08.070

    Article  CAS  PubMed  Google Scholar 

  40. Rudick RA, Trapp BD (2009) Gray-matter injury in multiple sclerosis. N Engl J Med 361(15):1505–1506. https://doi.org/10.1056/NEJMcibr0905482

    Article  CAS  PubMed  Google Scholar 

  41. Romanelli E, Merkler D, Mezydlo A, Weil MT, Weber MS, Nikic I, Potz S, Meinl E et al (2016) Myelinosome formation represents an early stage of oligodendrocyte damage in multiple sclerosis and its animal model. Nat Commun 7:13275. https://doi.org/10.1038/ncomms13275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lazarowski ER, Shea DA, Boucher RC, Harden TK (2003) Release of cellular UDP-glucose as a potential extracellular signaling molecule. Mol Pharmacol 63(5):1190–1197

    Article  CAS  Google Scholar 

  43. Kreda SM, Seminario-Vidal L, Heusden C, Lazarowski ER (2008) Thrombin-promoted release of UDP-glucose from human astrocytoma cells. Br J Pharmacol 153(7):1528–1537. https://doi.org/10.1038/sj.bjp.0707692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Skripuletz T, Hackstette D, Bauer K, Gudi V, Pul R, Voss E, Berger K, Kipp M et al (2013) Astrocytes regulate myelin clearance through recruitment of microglia during cuprizone-induced demyelination. Brain J Neurol 136(Pt 1):147–167. https://doi.org/10.1093/brain/aws262

    Article  Google Scholar 

  45. Grosse-Veldmann R, Becker B, Amor S, van der Valk P, Beyer C, Kipp M (2016) Lesion expansion in experimental demyelination animal models and multiple sclerosis lesions. Mol Neurobiol 53(7):4905–4917. https://doi.org/10.1007/s12035-015-9420-y

    Article  CAS  PubMed  Google Scholar 

  46. van Horssen J, Singh S, van der Pol S, Kipp M, Lim JL, Peferoen L, Gerritsen W, Kooi EJ et al (2012) Clusters of activated microglia in normal-appearing white matter show signs of innate immune activation. J Neuroinflammation 9:156. https://doi.org/10.1186/1742-2094-9-156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Lassmann H, van Horssen J, Mahad D (2012) Progressive multiple sclerosis: pathology and pathogenesis. Nat Rev Neurol 8(11):647–656. https://doi.org/10.1038/nrneurol.2012.168

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by UCB BioPharma (Braine L’Alleud, Belgium), the Dr. Robert Pfleger Stiftung (M.K.), and the Deutsche Forschungsgemeinschaft (KI 1469/8-1). The technical support, H. Helten, P. Ibold, A. Baltruschat, B. Aschauer, JM. Frequin, and M. Caruso, are acknowledged.

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Authors and Affiliations

  1. Institute of Neuroanatomy and JARA-BRAIN, Faculty of Medicine, RWTH Aachen University, 52074, Aachen, Germany

    Stella Nyamoya, Birte Becker & Cordian Beyer

  2. Department of Anatomy II, Ludwig-Maximilians-University of Munich, 80336, Munich, Germany

    Stella Nyamoya, Patrizia Leopold, Christoph Schmitz & Markus Kipp

  3. Neurosciences TA Biology, UCB BioPharma, Braine L’Alleud, Brussels, Belgium

    Fabian Hustadt & Anne Michel

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  1. Stella Nyamoya
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  2. Patrizia Leopold
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Correspondence to Markus Kipp.

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Main Points

1. Cortical remyelination is delayed in the cuprizone model.

2. GPR17 expression is induced in the white but not gray matter.

3. GPR17 expression is induced in acute, but not chronic lesions.

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Supplementary figure 1

Results of anti-GPR17 antibody optimization. Representative pictures illustrate results of standard heat induced epitome retrieval (HIER) of brain tissues stained with anti-GRP17 antibodies. Tissue sections were either cooked in Tris/EDTA buffer (pH 9.0) or citrate (pH 6.0) buffer for 10 or 20 min, receptively. In parallel, one slide was not subjected to HIER. Arrowheads indicate GPR17+ cells in the cortex. (GIF 482 kb)

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Nyamoya, S., Leopold, P., Becker, B. et al. G-Protein-Coupled Receptor Gpr17 Expression in Two Multiple Sclerosis Remyelination Models. Mol Neurobiol 56, 1109–1123 (2019). https://doi.org/10.1007/s12035-018-1146-1

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