Skip to main content

Advertisement

SpringerLink
Log in

Extracellular Purine Metabolism—Potential Target in Multiple Sclerosis

  • Reviews
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

The purinergic signaling system comprises a complex network of extracellular purines and purine-metabolizing ectoenzymes, nucleotide and nucleoside receptors, ATP release channels, and nucleoside transporters. Because of its immunomodulatory function, this system is critically involved in the pathogenesis of multiple sclerosis (MS) and its best-characterized animal model, experimental autoimmune encephalomyelitis (EAE). MS is a chronic neuroinflammatory demyelinating and neurodegenerative disease with autoimmune etiology and great heterogeneity, mostly affecting young adults and leading to permanent disability. In MS/EAE, alterations were detected in almost all components of the purinergic signaling system in both peripheral immune cells and central nervous system (CNS) glial cells, which play an important role in the pathogenesis of the disease. A decrease in extracellular ATP levels and an increase in its downstream metabolites, particularly adenosine and inosine, were frequently observed at MS, indicating a shift in metabolism toward an anti-inflammatory environment. Accordingly, upregulation of the major ectonucleotidase tandem CD39/CD73 was detected in the blood cells and CNS of relapsing–remitting MS patients. Based on the postulated role of A2A receptors in the transition from acute to chronic neuroinflammation, the association of variants of the adenosine deaminase gene with the severity of MS, and the beneficial effects of inosine treatment in EAE, the adenosinergic system emerged as a promising target in neuroinflammation. More recently, several publications have identified ADP-dependent P2Y12 receptors and the major extracellular ADP producing enzyme nucleoside triphosphate diphosphohydrolase 2 (NTPDase2) as novel potential targets in MS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

Data Availability

Not applicable.

References

  1. Burnstock G (1972) Purinergic nerves. Pharmacol Rev 24(3):509–581

    CAS  PubMed  Google Scholar 

  2. Di Virgilio F, Vultaggio-Poma V, Falzoni S, Giuliani AL (2023) Extracellular ATP: a powerful inflammatory mediator in the central nervous system. Neuropharmacology 224:109333. https://doi.org/10.1016/j.neuropharm.2022.109333

    Article  CAS  PubMed  Google Scholar 

  3. Fiebich BL, Akter S, Akundi RS (2014) The two-hit hypothesis for neuroinflammation: role of exogenous ATP in modulating inflammation in the brain. Front Cell Neurosci 8:260. https://doi.org/10.3389/fncel.2014.00260

    Article  PubMed  PubMed Central  Google Scholar 

  4. Sperlágh B, Vizi SE (1996) Neuronal synthesis, storage and release of ATP. Semin Neurosci 8(4):175–186. https://doi.org/10.1006/smns.1996.0023

    Article  Google Scholar 

  5. Ionescu MI (2019) Adenylate kinase: a ubiquitous enzyme correlated with medical conditions. Protein J 38(2):120–133. https://doi.org/10.1007/s10930-019-09811-0

    Article  CAS  PubMed  Google Scholar 

  6. Bonora M, Patergnani S, Rimessi A, De Marchi E, Suski JM, Bononi A, Giorgi C, Marchi S et al (2012) ATP synthesis and storage. Purinergic Signal 8(3):343–357. https://doi.org/10.1007/s11302-012-9305-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Ruprecht JJ, King MS, Zögg T, Aleksandrova AA, Pardon E, Crichton PG, Steyaert J, Kunji ERS (2019) The molecular mechanism of transport by the mitochondrial ADP/ATP carrier. Cell 176(3):435-447.e415. https://doi.org/10.1016/j.cell.2018.11.025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Greiner JV, Glonek T (2021) Intracellular ATP concentration and implication for cellular evolution. Biology 10(11). https://doi.org/10.3390/biology10111166

  9. Matuszczyk JC, Teleki A, Pfizenmaier J, Takors R (2015) Compartment-specific metabolomics for CHO reveals that ATP pools in mitochondria are much lower than in cytosol. Biotechnol J 10(10):1639–1650. https://doi.org/10.1002/biot.201500060

    Article  CAS  PubMed  Google Scholar 

  10. Harada K, Kamiya T, Tsuboi T (2015) Gliotransmitter release from astrocytes: functional, developmental, and pathological implications in the brain. Front Neurosci 9:499. https://doi.org/10.3389/fnins.2015.00499

    Article  PubMed  Google Scholar 

  11. Burnstock G (2001) Purine-mediated signalling in pain and visceral perception. Trends Pharmacol Sci 22(4):182–188. https://doi.org/10.1016/s0165-6147(00)01643-6

    Article  CAS  PubMed  Google Scholar 

  12. Burnstock G (1995) Noradrenaline and ATP: cotransmitters and neuromodulators. J Physiol Pharmacol 46(4):365–384

    CAS  PubMed  Google Scholar 

  13. Burnstock G (2013) Purinergic signalling in the lower urinary tract. Acta Physiol (Oxf) 207(1):40–52. https://doi.org/10.1111/apha.12012

    Article  CAS  PubMed  Google Scholar 

  14. Yegutkin GG (2008) Nucleotide- and nucleoside-converting ectoenzymes: Important modulators of purinergic signalling cascade. Biochem Biophys Acta 1783(5):673–694. https://doi.org/10.1016/j.bbamcr.2008.01.024

    Article  CAS  PubMed  Google Scholar 

  15. Lazarowski ER, Boucher RC, Harden TK (2000) Constitutive release of ATP and evidence for major contribution of ecto-nucleotide pyrophosphatase and nucleoside diphosphokinase to extracellular nucleotide concentrations. J Biol Chem 275(40):31061–31068. https://doi.org/10.1074/jbc.M003255200

    Article  CAS  PubMed  Google Scholar 

  16. Okada SF, Nicholas RA, Kreda SM, Lazarowski ER, Boucher RC (2006) Physiological regulation of ATP release at the apical surface of human airway epithelia. J Biol Chem 281(32):22992–23002. https://doi.org/10.1074/jbc.M603019200

    Article  CAS  PubMed  Google Scholar 

  17. Scemes E, Suadicani SO, Dahl G, Spray DC (2007) Connexin and pannexin mediated cell-cell communication. Neuron Glia Biol 3(3):199–208. https://doi.org/10.1017/s1740925x08000069

    Article  PubMed  PubMed Central  Google Scholar 

  18. Taruno A (2018) ATP Release Channels. Int J Mol Sci 19(3). https://doi.org/10.3390/ijms19030808

  19. Sabirov RZ, Okada Y (2005) ATP release via anion channels. Purinergic Signal 1(4):311–328. https://doi.org/10.1007/s11302-005-1557-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Masuda T, Ozono Y, Mikuriya S, Kohro Y, Tozaki-Saitoh H, Iwatsuki K, Uneyama H, Ichikawa R et al (2016) Dorsal horn neurons release extracellular ATP in a VNUT-dependent manner that underlies neuropathic pain. Nat Commun 7:12529. https://doi.org/10.1038/ncomms12529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Pankratov Y, Lalo U, Verkhratsky A, North RA (2007) Quantal release of ATP in mouse cortex. J Gen Physiol 129(3):257–265. https://doi.org/10.1085/jgp.200609693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Bowser DN, Khakh BS (2007) Vesicular ATP is the predominant cause of intercellular calcium waves in astrocytes. J Gen Physiol 129(6):485–491. https://doi.org/10.1085/jgp.200709780

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Bodin P, Burnstock G (2001) Purinergic signalling: ATP release. Neurochem Res 26(8–9):959–969. https://doi.org/10.1023/a:1012388618693

    Article  CAS  PubMed  Google Scholar 

  24. Bours MJ, Swennen EL, Di Virgilio F, Cronstein BN, Dagnelie PC (2006) Adenosine 5’-triphosphate and adenosine as endogenous signaling molecules in immunity and inflammation. Pharmacol Ther 112(2):358–404. https://doi.org/10.1016/j.pharmthera.2005.04.013

    Article  CAS  PubMed  Google Scholar 

  25. Pedata F, Dettori I, Coppi E, Melani A, Fusco I, Corradetti R, Pugliese AM (2016) Purinergic signalling in brain ischemia. Neuropharmacology 104:105–130. https://doi.org/10.1016/j.neuropharm.2015.11.007

    Article  CAS  PubMed  Google Scholar 

  26. Zimmermann H (1996) Biochemistry, localization and functional roles of ecto-nucleotidases in the nervous system. Prog Neurobiol 49(6):589–618. https://doi.org/10.1016/0301-0082(96)00026-3

    Article  CAS  PubMed  Google Scholar 

  27. Zimmermann H, Zebisch M, Sträter N (2012) Cellular function and molecular structure of ecto-nucleotidases. Purinergic Signal 8(3):437–502. https://doi.org/10.1007/s11302-012-9309-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Yegutkin GG (2014) Enzymes involved in metabolism of extracellular nucleotides and nucleosides: functional implications and measurement of activities. Crit Rev Biochem Mol Biol 49(6):473–497. https://doi.org/10.3109/10409238.2014.953627

    Article  CAS  PubMed  Google Scholar 

  29. Maiuolo J, Oppedisano F, Gratteri S, Muscoli C, Mollace V (2016) Regulation of uric acid metabolism and excretion. Int J Cardiol 213:8–14. https://doi.org/10.1016/j.ijcard.2015.08.109

    Article  PubMed  Google Scholar 

  30. Robson SC, Sévigny J, Zimmermann H (2006) The E-NTPDase family of ectonucleotidases: structure function relationships and pathophysiological significance. Purinergic Signal 2(2):409–430. https://doi.org/10.1007/s11302-006-9003-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wink MR, Braganhol E, Tamajusuku AS, Lenz G, Zerbini LF, Libermann TA, Sévigny J, Battastini AM et al (2006) Nucleoside triphosphate diphosphohydrolase-2 (NTPDase2/CD39L1) is the dominant ectonucleotidase expressed by rat astrocytes. Neuroscience 138(2):421–432. https://doi.org/10.1016/j.neuroscience.2005.11.039

    Article  CAS  PubMed  Google Scholar 

  32. Maliszewski CR, Delespesse GJ, Schoenborn MA, Armitage RJ, Fanslow WC, Nakajima T, Baker E, Sutherland GR et al (1994) The CD39 lymphoid cell activation antigen. Molecular cloning and structural characterization. J Immunol (Baltimore, Md: 1950) 153(8):3574–3583

    Article  CAS  Google Scholar 

  33. Kaczmarek E, Koziak K, Sévigny J, Siegel JB, Anrather J, Beaudoin AR, Bach FH, Robson SC (1996) Identification and characterization of CD39/vascular ATP diphosphohydrolase. J Biol Chem 271(51):33116–33122. https://doi.org/10.1074/jbc.271.51.33116

    Article  CAS  PubMed  Google Scholar 

  34. Stout JG, Kirley TL (1996) Control of cell membrane ecto-ATPase by oligomerization state: intermolecular cross-linking modulates ATPase activity. Biochemistry 35(25):8289–8298. https://doi.org/10.1021/bi960563g

    Article  CAS  PubMed  Google Scholar 

  35. Coade SB, Pearson JD (1989) Metabolism of adenine nucleotides in human blood. Circ Res 65(3):531–537. https://doi.org/10.1161/01.res.65.3.531

    Article  CAS  PubMed  Google Scholar 

  36. Yegutkin GG, Wieringa B, Robson SC, Jalkanen S (2012) Metabolism of circulating ADP in the bloodstream is mediated via integrated actions of soluble adenylate kinase-1 and NTPDase1/CD39 activities. FASEB J 26(9):3875–3883. https://doi.org/10.1096/fj.12-205658

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Visovatti SH, Hyman MC, Bouis D, Neubig R, McLaughlin VV, Pinsky DJ (2012) Increased CD39 nucleotidase activity on microparticles from patients with idiopathic pulmonary arterial hypertension. PLoS ONE 7(7):e40829. https://doi.org/10.1371/journal.pone.0040829

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Kukulski F, Lévesque SA, Lavoie EG, Lecka J, Bigonnesse F, Knowles AF, Robson SC, Kirley TL et al (2005) Comparative hydrolysis of P2 receptor agonists by NTPDases 1, 2, 3 and 8. Purinergic Signal 1(2):193–204. https://doi.org/10.1007/s11302-005-6217-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Zarrinmayeh H, Territo PR (2020) Purinergic receptors of the central nervous system: biology, PET ligands, and their applications. Mol Imaging 19:1536012120927609. https://doi.org/10.1177/1536012120927609

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Braun N, Sévigny J, Robson SC, Enjyoji K, Guckelberger O, Hammer K, Di Virgilio F, Zimmermann H (2000) Assignment of ecto-nucleoside triphosphate diphosphohydrolase-1/cd39 expression to microglia and vasculature of the brain. Eur J Neurosci 12(12):4357–4366

    CAS  PubMed  Google Scholar 

  41. Enjyoji K, Sévigny J, Lin Y, Frenette PS, Christie PD, Esch JS 2nd, Imai M, Edelberg JM et al (1999) Targeted disruption of cd39/ATP diphosphohydrolase results in disordered hemostasis and thromboregulation. Nat Med 5(9):1010–1017. https://doi.org/10.1038/12447

    Article  CAS  PubMed  Google Scholar 

  42. Marcus AJ, Broekman MJ, Drosopoulos JH, Islam N, Pinsky DJ, Sesti C, Levi R (2003) Heterologous cell-cell interactions: thromboregulation, cerebroprotection and cardioprotection by CD39 (NTPDase-1). J Thromb Haemost: JTH 1(12):2497–2509. https://doi.org/10.1111/j.1538-7836.2003.00479.x

    Article  CAS  PubMed  Google Scholar 

  43. Dwyer KM, Deaglio S, Gao W, Friedman D, Strom TB, Robson SC (2007) CD39 and control of cellular immune responses. Purinergic Signal 3(1–2):171–180. https://doi.org/10.1007/s11302-006-9050-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Allard B, Longhi MS, Robson SC, Stagg J (2017) The ectonucleotidases CD39 and CD73: novel checkpoint inhibitor targets. Immunol Rev 276(1):121–144. https://doi.org/10.1111/imr.12528

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Borsellino G, Kleinewietfeld M, Di Mitri D, Sternjak A, Diamantini A, Giometto R, Höpner S, Centonze D et al (2007) Expression of ectonucleotidase CD39 by Foxp3+ Treg cells: hydrolysis of extracellular ATP and immune suppression. Blood 110(4):1225–1232. https://doi.org/10.1182/blood-2006-12-064527

    Article  CAS  PubMed  Google Scholar 

  46. Färber K, Kettenmann H (2006) Purinergic signaling and microglia. Pflugers Arch 452(5):615–621. https://doi.org/10.1007/s00424-006-0064-7

    Article  CAS  PubMed  Google Scholar 

  47. Bynoe MS, Viret C, Yan A, Kim D-G (2015) Adenosine receptor signaling: a key to opening the blood–brain door. Fluids Barriers CNS 12(1):20. https://doi.org/10.1186/s12987-015-0017-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sévigny J, Sundberg C, Braun N, Guckelberger O, Csizmadia E, Qawi I, Imai M, Zimmermann H et al (2002) Differential catalytic properties and vascular topography of murine nucleoside triphosphate diphosphohydrolase 1 (NTPDase1) and NTPDase2 have implications for thromboregulation. Blood 99(8):2801–2809. https://doi.org/10.1182/blood.v99.8.2801

    Article  PubMed  Google Scholar 

  49. Cekic C, Linden J (2016) Purinergic regulation of the immune system. Nat Rev Immunol 16(3):177–192. https://doi.org/10.1038/nri.2016.4

    Article  CAS  PubMed  Google Scholar 

  50. Di Virgilio F, Ceruti S, Bramanti P, Abbracchio MP (2009) Purinergic signalling in inflammation of the central nervous system. Trends Neurosci 32(2):79–87. https://doi.org/10.1016/j.tins.2008.11.003

    Article  CAS  PubMed  Google Scholar 

  51. Wang TF, Guidotti G (1998) Widespread expression of ecto-apyrase (CD39) in the central nervous system. Brain Res 790(1–2):318–322. https://doi.org/10.1016/s0006-8993(97)01562-x

    Article  CAS  PubMed  Google Scholar 

  52. Braun N, Sévigny J, Mishra SK, Robson SC, Barth SW, Gerstberger R, Hammer K, Zimmermann H (2003) Expression of the ecto-ATPase NTPDase2 in the germinal zones of the developing and adult rat brain. Eur J Neurosci 17(7):1355–1364. https://doi.org/10.1046/j.1460-9568.2003.02567.x

    Article  PubMed  Google Scholar 

  53. Braun N, Sévigny J, Robson SC, Hammer K, Hanani M, Zimmermann H (2004) Association of the ecto-ATPase NTPDase2 with glial cells of the peripheral nervous system. Glia 45(2):124–132. https://doi.org/10.1002/glia.10309

    Article  PubMed  Google Scholar 

  54. Gampe K, Hammer K, Kittel Á, Zimmermann H (2012) The medial habenula contains a specific nonstellate subtype of astrocyte expressing the ectonucleotidase NTPDase2. Glia 60(12):1860–1870. https://doi.org/10.1002/glia.22402

    Article  PubMed  Google Scholar 

  55. Jakovljevic M, Lavrnja I, Bozic I, Savic D, Bjelobaba I, Pekovic S, Sévigny J, Nedeljkovic N et al (2017) Down-regulation of NTPDase2 and ADP-sensitive P2 purinoceptors correlate with severity of symptoms during experimental autoimmune encephalomyelitis. Front Cell Neurosci 11:333. https://doi.org/10.3389/fncel.2017.00333

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dragic M, Mihajlovic K, Adzic M, Jakovljevic M, Kontic MZ, Mitrović N, Laketa D, Lavrnja I et al (2022) Expression of ectonucleoside triphosphate diphosphohydrolase 2 (NTPDase2) is negatively regulated under neuroinflammatory conditions in vivo and in vitro. ASN Neuro 14:17590914221102068. https://doi.org/10.1177/17590914221102068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Lavoie EG, Gulbransen BD, Martín-Satué M, Aliagas E, Sharkey KA, Sévigny J (2011) Ectonucleotidases in the digestive system: focus on NTPDase3 localization. Am J Physiol Gastrointest Liver Physiol 300(4):G608-620. https://doi.org/10.1152/ajpgi.00207.2010

    Article  CAS  PubMed  Google Scholar 

  58. Shukla V, Zimmermann H, Wang L, Kettenmann H, Raab S, Hammer K, Sévigny J, Robson SC et al (2005) Functional expression of the ecto-ATPase NTPDase2 and of nucleotide receptors by neuronal progenitor cells in the adult murine hippocampus. J Neurosci Res 80(5):600–610. https://doi.org/10.1002/jnr.20508

    Article  CAS  PubMed  Google Scholar 

  59. Gampe K, Stefani J, Hammer K, Brendel P, Pötzsch A, Enikolopov G, Enjyoji K, Acker-Palmer A et al (2015) NTPDase2 and purinergic signaling control progenitor cell proliferation in neurogenic niches of the adult mouse brain. Stem Cells (Dayton, Ohio) 33(1):253–264. https://doi.org/10.1002/stem.1846

    Article  CAS  PubMed  Google Scholar 

  60. Domercq M, Zabala A, Matute C (2019) Purinergic receptors in multiple sclerosis pathogenesis. Brain Res Bull 151:38–45. https://doi.org/10.1016/j.brainresbull.2018.11.018

    Article  CAS  PubMed  Google Scholar 

  61. Belcher SM, Zsarnovszky A, Crawford PA, Hemani H, Spurling L, Kirley TL (2006) Immunolocalization of ecto-nucleoside triphosphate diphosphohydrolase 3 in rat brain: implications for modulation of multiple homeostatic systems including feeding and sleep-wake behaviors. Neuroscience 137(4):1331–1346. https://doi.org/10.1016/j.neuroscience.2005.08.086

    Article  CAS  PubMed  Google Scholar 

  62. Bollen M, Gijsbers R, Ceulemans H, Stalmans W, Stefan C (2000) Nucleotide pyrophosphatases/phosphodiesterases on the move. Crit Rev Biochem Mol Biol 35(6):393–432. https://doi.org/10.1080/10409230091169249

    Article  CAS  PubMed  Google Scholar 

  63. Borza R, Salgado-Polo F, Moolenaar WH, Perrakis A (2022) Structure and function of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family: tidying up diversity. J Biol Chem 298(2):101526. https://doi.org/10.1016/j.jbc.2021.101526

    Article  CAS  PubMed  Google Scholar 

  64. Stefan C, Jansen S, Bollen M (2005) NPP-type ectophosphodiesterases: unity in diversity. Trends Biochem Sci 30(10):542–550. https://doi.org/10.1016/j.tibs.2005.08.005

    Article  CAS  PubMed  Google Scholar 

  65. Lee SY, Müller CE (2017) Nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) and its inhibitors. MedChemComm 8(5):823–840. https://doi.org/10.1039/c7md00015d

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Goding JW, Grobben B, Slegers H (2003) Physiological and pathophysiological functions of the ecto-nucleotide pyrophosphatase/phosphodiesterase family. Biochem Biophys Acta 1638(1):1–19. https://doi.org/10.1016/s0925-4439(03)00058-9

    Article  CAS  PubMed  Google Scholar 

  67. Frittitta L, Camastra S, Baratta R, Costanzo BV, D’Adamo M, Graci S, Spampinato D, Maddux BA et al (1999) A soluble PC-1 circulates in human plasma: relationship with insulin resistance and associated abnormalities. J Clin Endocrinol Metab 84(10):3620–3625. https://doi.org/10.1210/jcem.84.10.6050

    Article  CAS  PubMed  Google Scholar 

  68. Kato K, Nishimasu H, Okudaira S, Mihara E, Ishitani R, Takagi J, Aoki J, Nureki O (2012) Crystal structure of Enpp1, an extracellular glycoprotein involved in bone mineralization and insulin signaling. Proc Natl Acad Sci 109(42):16876–16881. https://doi.org/10.1073/pnas.1208017109

    Article  PubMed  PubMed Central  Google Scholar 

  69. Bjelobaba I, Nedeljkovic N, Subasic S, Lavrnja I, Pekovic S, Stojkov D, Rakic L, Stojiljkovic M (2006) Immunolocalization of ecto-nucleotide pyrophosphatase/phosphodiesterase 1 (NPP1) in the rat forebrain. Brain Res 1120(1):54–63. https://doi.org/10.1016/j.brainres.2006.08.114

    Article  CAS  PubMed  Google Scholar 

  70. Magkrioti C, Galaris A, Kanellopoulou P, Stylianaki EA, Kaffe E, Aidinis V (2019) Autotaxin and chronic inflammatory diseases. J Autoimmun 104:102327. https://doi.org/10.1016/j.jaut.2019.102327

    Article  CAS  PubMed  Google Scholar 

  71. Yung YC, Stoddard NC, Mirendil H, Chun J (2015) Lysophosphatidic acid signaling in the nervous system. Neuron 85(4):669–682. https://doi.org/10.1016/j.neuron.2015.01.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Jansen S, Stefan C, Creemers JW, Waelkens E, Van Eynde A, Stalmans W, Bollen M (2005) Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. J Cell Sci 118(Pt 14):3081–3089. https://doi.org/10.1242/jcs.02438

    Article  CAS  PubMed  Google Scholar 

  73. Zhang Y, Chen YC, Krummel MF, Rosen SD (2012) Autotaxin through lysophosphatidic acid stimulates polarization, motility, and transendothelial migration of naive T cells. J Immunol (Baltimore, Md: 1950) 189(8):3914–3924. https://doi.org/10.4049/jimmunol.1201604

    Article  CAS  Google Scholar 

  74. Blass-Kampmann S, Kindler-Röhrborn A, Deissler H, D’Urso D, Rajewsky MF (1997) In vitro differentiation of neural progenitor cells from prenatal rat brain: common cell surface glycoprotein on three glial cell subsets. J Neurosci Res 48(2):95–111. https://doi.org/10.1002/(sici)1097-4547(19970415)48:2%3c95::aid-jnr2%3e3.0.co;2-7

    Article  CAS  PubMed  Google Scholar 

  75. Fuss B, Baba H, Phan T, Tuohy VK, Macklin WB (1997) Phosphodiesterase I, a novel adhesion molecule and/or cytokine involved in oligodendrocyte function. J Neurosci 17(23):9095–9103. https://doi.org/10.1523/jneurosci.17-23-09095.1997

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Xiang Z, Burnstock G (2005) Expression of P2X receptors in rat choroid plexus. NeuroReport 16(9):903–907. https://doi.org/10.1097/00001756-200506210-00006

    Article  CAS  PubMed  Google Scholar 

  77. Zimmermann H (2006) Nucleotide signaling in nervous system development. Pflugers Arch 452(5):573–588. https://doi.org/10.1007/s00424-006-0067-4

    Article  CAS  PubMed  Google Scholar 

  78. Cognato Gde P, Czepielewski RS, Sarkis JJ, Bogo MR, Bonan CD (2008) Expression mapping of ectonucleotide pyrophosphatase/phosphodiesterase 1–3 (E-NPP1-3) in different brain structures during rat development. Int J Dev Neurosci 26(6):593–598. https://doi.org/10.1016/j.ijdevneu.2008.05.001

    Article  CAS  PubMed  Google Scholar 

  79. Albright RA, Ornstein DL, Cao W, Chang WC, Robert D, Tehan M, Hoyer D, Liu L et al (2014) Molecular basis of purinergic signal metabolism by ectonucleotide pyrophosphatase/phosphodiesterases 4 and 1 and implications in stroke. J Biol Chem 289(6):3294–3306. https://doi.org/10.1074/jbc.M113.505867

    Article  CAS  PubMed  Google Scholar 

  80. Woehrle T, Ledderose C, Rink J, Slubowski C, Junger WG (2019) Autocrine stimulation of P2Y1 receptors is part of the purinergic signaling mechanism that regulates T cell activation. Purinergic Signal 15(2):127–137. https://doi.org/10.1007/s11302-019-09653-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Albayati S, Vemulapalli H, Tsygankov AY, Liverani E (2021) P2Y(12) antagonism results in altered interactions between platelets and regulatory T cells during sepsis. J Leukoc Biol 110(1):141–153. https://doi.org/10.1002/jlb.3a0220-097r

    Article  CAS  PubMed  Google Scholar 

  82. Amoafo EB, Entsie P, Albayati S, Dorsam GP, Kunapuli SP, Kilpatrick LE, Liverani E (2022) Sex-related differences in the response of anti-platelet drug therapies targeting purinergic signaling pathways in sepsis. Front Immunol 13. https://doi.org/10.3389/fimmu.2022.1015577

  83. Hoylaerts MF, Manes T, Millán JL (1997) Mammalian alkaline phosphatases are allosteric enzymes. J Biol Chem 272(36):22781–22787. https://doi.org/10.1074/jbc.272.36.22781

    Article  CAS  PubMed  Google Scholar 

  84. Millán JL (2006) Alkaline phosphatases : structure, substrate specificity and functional relatedness to other members of a large superfamily of enzymes. Purinergic Signal 2(2):335–341. https://doi.org/10.1007/s11302-005-5435-6

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Stigbrand T (1984) Present status and future trends of human alkaline phosphatases. Prog Clin Biol Res 166:3–14

    CAS  PubMed  Google Scholar 

  86. Langer D, Ikehara Y, Takebayashi H, Hawkes R, Zimmermann H (2007) The ectonucleotidases alkaline phosphatase and nucleoside triphosphate diphosphohydrolase 2 are associated with subsets of progenitor cell populations in the mouse embryonic, postnatal and adult neurogenic zones. Neuroscience 150(4):863–879. https://doi.org/10.1016/j.neuroscience.2007.07.064

    Article  CAS  PubMed  Google Scholar 

  87. Burnstock G, Knight GE (2004) Cellular distribution and functions of P2 receptor subtypes in different systems. Int Rev Cytol 240:31–304. https://doi.org/10.1016/s0074-7696(04)40002-3

    Article  CAS  PubMed  Google Scholar 

  88. Deracinois B, Lenfant AM, Dehouck MP, Flahaut C (2015) Tissue non-specific alkaline phosphatase (TNAP) in vessels of the brain. Subcell Biochem 76:125–151. https://doi.org/10.1007/978-94-017-7197-9_7

    Article  CAS  PubMed  Google Scholar 

  89. Díaz-Hernández M, Gómez-Ramos A, Rubio A, Gómez-Villafuertes R, Naranjo JR, Miras-Portugal MT, Avila J (2010) Tissue-nonspecific alkaline phosphatase promotes the neurotoxicity effect of extracellular tau. J Biol Chem 285(42):32539–32548. https://doi.org/10.1074/jbc.M110.145003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Nakazato H, Deguchi M, Fujimoto M, Fukushima H (1997) Alkaline phosphatase expression in cultured endothelial cells of aorta and brain microvessels: induction by interleukin-6-type cytokines and suppression by transforming growth factor betas. Life Sci 61(20):2065–2072. https://doi.org/10.1016/s0024-3205(97)00865-5

    Article  CAS  PubMed  Google Scholar 

  91. Graser S, Liedtke D, Jakob F (2021) TNAP as a new player in chronic inflammatory conditions and metabolism. Int J Mol Sci 22(2). https://doi.org/10.3390/ijms22020919

  92. Sträter N (2006) Ecto-5’-nucleotidase: structure function relationships. Purinergic Signal 2(2):343–350. https://doi.org/10.1007/s11302-006-9000-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Zimmermann H (1992) 5’-Nucleotidase: molecular structure and functional aspects. Biochem J 285((Pt 2)):345–365. https://doi.org/10.1042/bj2850345

    Article  MathSciNet  CAS  PubMed  PubMed Central  Google Scholar 

  94. Suzuki K, Furukawa Y, Tamura H, Ejiri N, Suematsu H, Taguchi R, Nakamura S, Suzuki Y et al (1993) Purification and cDNA cloning of bovine liver 5’-nucleotidase, a GPI-anchored protein, and its expression in COS cells. J Biochem 113(5):607–613. https://doi.org/10.1093/oxfordjournals.jbchem.a124090

    Article  CAS  PubMed  Google Scholar 

  95. Koszalka P, Ozüyaman B, Huo Y, Zernecke A, Flögel U, Braun N, Buchheiser A, Decking UK et al (2004) Targeted disruption of cd73/ecto-5’-nucleotidase alters thromboregulation and augments vascular inflammatory response. Circ Res 95(8):814–821. https://doi.org/10.1161/01.RES.0000144796.82787.6f

    Article  CAS  PubMed  Google Scholar 

  96. Ohta M, Toyama K, Gutterman DD, Campbell WB, Lemaître V, Teraoka R, Miura H (2013) Ecto-5’-nucleotidase, CD73, is an endothelium-derived hyperpolarizing factor synthase. Arterioscler Thromb Vasc Biol 33(3):629–636. https://doi.org/10.1161/atvbaha.112.300600

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Kulesskaya N, Võikar V, Peltola M, Yegutkin GG, Salmi M, Jalkanen S, Rauvala H (2013) CD73 is a major regulator of adenosinergic signalling in mouse brain. PLoS ONE 8(6):e66896. https://doi.org/10.1371/journal.pone.0066896

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Sowa NA, Taylor-Blake B, Zylka MJ (2010) Ecto-5’-nucleotidase (CD73) inhibits nociception by hydrolyzing AMP to adenosine in nociceptive circuits. J Neurosci 30(6):2235–2244. https://doi.org/10.1523/jneurosci.5324-09.2010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Mills JH, Thompson LF, Mueller C, Waickman AT, Jalkanen S, Niemela J, Airas L, Bynoe MS (2008) CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci USA 105(27):9325–9330. https://doi.org/10.1073/pnas.0711175105

    Article  PubMed  PubMed Central  Google Scholar 

  100. Airas L, Hellman J, Salmi M, Bono P, Puurunen T, Smith DJ, Jalkanen S (1995) CD73 is involved in lymphocyte binding to the endothelium: characterization of lymphocyte-vascular adhesion protein 2 identifies it as CD73. J Exp Med 182(5):1603–1608. https://doi.org/10.1084/jem.182.5.1603

    Article  CAS  PubMed  Google Scholar 

  101. Adzic M, Nedeljkovic N (2018) Unveiling the role of Ecto-5′-Nucleotidase/CD73 in astrocyte migration by using pharmacological tools. Front Pharmacol 9. https://doi.org/10.3389/fphar.2018.00153

  102. Resta R, Yamashita Y, Thompson LF (1998) Ecto-enzyme and signaling functions of lymphocyte CD73. Immunol Rev 161:95–109. https://doi.org/10.1111/j.1600-065x.1998.tb01574.x

    Article  CAS  PubMed  Google Scholar 

  103. Deaglio S, Dwyer KM, Gao W, Friedman D, Usheva A, Erat A, Chen JF, Enjyoji K et al (2007) Adenosine generation catalyzed by CD39 and CD73 expressed on regulatory T cells mediates immune suppression. J Exp Med 204(6):1257–1265. https://doi.org/10.1084/jem.20062512

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Dunwiddie TV, Masino SA (2001) The role and regulation of adenosine in the central nervous system. Annu Rev Neurosci 24:31–55. https://doi.org/10.1146/annurev.neuro.24.1.31

    Article  CAS  PubMed  Google Scholar 

  105. Boison D (2013) Adenosine kinase: exploitation for therapeutic gain. Pharmacol Rev 65(3):906–943. https://doi.org/10.1124/pr.112.006361

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Fredholm BB (2007) Adenosine, an endogenous distress signal, modulates tissue damage and repair. Cell Death Differ 14(7):1315–1323. https://doi.org/10.1038/sj.cdd.4402132

    Article  CAS  PubMed  Google Scholar 

  107. Pastor-Anglada M, Pérez-Torras S (2018) Who is who in adenosine transport. Front Pharmacol 9:627. https://doi.org/10.3389/fphar.2018.00627

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Löffler M, Morote-Garcia JC, Eltzschig SA, Coe IR, Eltzschig HK (2007) Physiological roles of vascular nucleoside transporters. Arterioscler Thromb Vasc Biol 27(5):1004–1013. https://doi.org/10.1161/atvbaha.106.126714

    Article  PubMed  Google Scholar 

  109. Haskó G, Pacher P, Vizi ES, Illes P (2005) Adenosine receptor signaling in the brain immune system. Trends Pharmacol Sci 26(10):511–516. https://doi.org/10.1016/j.tips.2005.08.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Pastor-Anglada M, Pérez-Torras S (2018) Emerging roles of nucleoside transporters. Front Pharmacol 9:606. https://doi.org/10.3389/fphar.2018.00606

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Jakovljevic M, Lavrnja I, Bozic I, Milosevic A, Bjelobaba I, Savic D, Sévigny J, Pekovic S et al (2019) Induction of NTPDase1/CD39 by reactive microglia and macrophages is associated with the functional state during EAE. Front Neurosci 13:410. https://doi.org/10.3389/fnins.2019.00410

    Article  PubMed  PubMed Central  Google Scholar 

  112. Lavrnja I, Laketa D, Savic D, Bozic I, Bjelobaba I, Pekovic S, Nedeljkovic N (2015) Expression of a second ecto-5’-nucleotidase variant besides the usual protein in symptomatic phase of experimental autoimmune encephalomyelitis. J Mol Neurosci: MN 55(4):898–911. https://doi.org/10.1007/s12031-014-0445-x

    Article  CAS  PubMed  Google Scholar 

  113. Zavialov AV, Engström A (2005) Human ADA2 belongs to a new family of growth factors with adenosine deaminase activity. Biochem J 391(Pt 1):51–57. https://doi.org/10.1042/bj20050683

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Franco R, Valenzuela A, Lluis C, Blanco J (1998) Enzymatic and extraenzymatic role of ecto-adenosine deaminase in lymphocytes. Immunol Rev 161:27–42. https://doi.org/10.1111/j.1600-065x.1998.tb01569.x

    Article  CAS  PubMed  Google Scholar 

  115. Pacheco R, Martinez-Navio JM, Lejeune M, Climent N, Oliva H, Gatell JM, Gallart T, Mallol J et al (2005) CD26, adenosine deaminase, and adenosine receptors mediate costimulatory signals in the immunological synapse. Proc Natl Acad Sci USA 102(27):9583–9588. https://doi.org/10.1073/pnas.0501050102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gorrell MD, Gysbers V, McCaughan GW (2001) CD26: a multifunctional integral membrane and secreted protein of activated lymphocytes. Scand J Immunol 54(3):249–264. https://doi.org/10.1046/j.1365-3083.2001.00984.x

    Article  CAS  PubMed  Google Scholar 

  117. Kaljas Y, Liu C, Skaldin M, Wu C, Zhou Q, Lu Y, Aksentijevich I, Zavialov AV (2017) Human adenosine deaminases ADA1 and ADA2 bind to different subsets of immune cells. Cell Mol Life Sci 74(3):555–570. https://doi.org/10.1007/s00018-016-2357-0

    Article  CAS  PubMed  Google Scholar 

  118. Gao ZW, Wang X, Lin F, Dong K (2022) Total adenosine deaminase highly correlated with adenosine deaminase 2 activity in serum. Ann Rheum Dis 81(2):e30. https://doi.org/10.1136/annrheumdis-2020-217007

    Article  PubMed  Google Scholar 

  119. Iwaki-Egawa S, Yamamoto T, Watanabe Y (2006) Human plasma adenosine deaminase 2 is secreted by activated monocytes. Biol Chem 387(3):319–321. https://doi.org/10.1515/bc.2006.042

    Article  CAS  PubMed  Google Scholar 

  120. Conlon BA, Law WR (2004) Macrophages are a source of extracellular adenosine deaminase-2 during inflammatory responses. Clin Exp Immunol 138(1):14–20. https://doi.org/10.1111/j.1365-2249.2004.02591.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Chechik BE, Schrader WP, Minowada J (1981) An immunomorphologic study of adenosine deaminase distribution in human thymus tissue, normal lymphocytes, and hematopoietic cell lines. J Immunol (Baltimore, Md: 1950) 126(3):1003–1007

    Article  CAS  Google Scholar 

  122. Wakade AR, Kulkarni JS, Fujii JT (1998) 2’-Deoxyadenosine selectively kills nonneuronal cells without affecting survival and growth of chick dorsal root ganglion neurons. Brain Res 788(1–2):69–79. https://doi.org/10.1016/s0006-8993(97)01514-x

    Article  CAS  PubMed  Google Scholar 

  123. Aldrich MB, Blackburn MR, Kellems RE (2000) The importance of adenosine deaminase for lymphocyte development and function. Biochem Biophys Res Commun 272(2):311–315. https://doi.org/10.1006/bbrc.2000.2773

    Article  CAS  PubMed  Google Scholar 

  124. Desrosiers MD, Cembrola KM, Fakir MJ, Stephens LA, Jama FM, Shameli A, Mehal WZ, Santamaria P et al (2007) Adenosine deamination sustains dendritic cell activation in inflammation. J Immunol (Baltimore, Md: 1950) 179(3):1884–1892. https://doi.org/10.4049/jimmunol.179.3.1884

    Article  CAS  Google Scholar 

  125. Nagy JI, LaBella LA, Buss M, Daddona PE (1984) Immunohistochemistry of adenosine deaminase: implications for adenosine neurotransmission. Science (New York, NY) 224(4645):166–168. https://doi.org/10.1126/science.6142530

    Article  CAS  Google Scholar 

  126. Melani A, Pantoni L, Corsi C, Bianchi L, Monopoli A, Bertorelli R, Pepeu G, Pedata F (1999) Striatal outflow of adenosine, excitatory amino acids, gamma-aminobutyric acid, and taurine in awake freely moving rats after middle cerebral artery occlusion: correlations with neurological deficit and histopathological damage. Stroke 30(11):2448–2454. https://doi.org/10.1161/01.str.30.11.2448. (discussion 2455)

    Article  CAS  PubMed  Google Scholar 

  127. Tamura R, Ohta H, Satoh Y, Nonoyama S, Nishida Y, Nibuya M (2016) Neuroprotective effects of adenosine deaminase in the striatum. J Cereb Blood Flow Metab 36(4):709–720. https://doi.org/10.1177/0271678x15625077

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Toro A, Paiva M, Ackerley C, Grunebaum E (2006) Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro. Cell Immunol 240(2):107–115. https://doi.org/10.1016/j.cellimm.2006.07.003

    Article  CAS  PubMed  Google Scholar 

  129. Bzowska A, Kulikowska E, Shugar D (2000) Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol Ther 88(3):349–425. https://doi.org/10.1016/S0163-7258(00)00097-8

    Article  CAS  PubMed  Google Scholar 

  130. Zamzow CR, Xiong W, Parkinson FE (2008) Adenosine produced by neurons is metabolized to hypoxanthine by astrocytes. J Neurosci Res 86(15):3447–3455. https://doi.org/10.1002/jnr.21789

    Article  CAS  PubMed  Google Scholar 

  131. Dalmau I, Vela JM, González B, Castellano B (1998) Expression of purine metabolism-related enzymes by microglial cells in the developing rat brain. J Comp Neurol 398(3):333–346. https://doi.org/10.1002/(sici)1096-9861(19980831)398:3%3c333::aid-cne3%3e3.0.co;2-0

    Article  CAS  PubMed  Google Scholar 

  132. Uhlen M, Karlsson MJ, Zhong W, Tebani A, Pou C, Mikes J, Lakshmikanth T, Forsström B et al (2019) A genome-wide transcriptomic analysis of protein-coding genes in human blood cells. Science (New York, NY) 366(6472):eaax9198. https://doi.org/10.1126/science.aax9198

    Article  CAS  Google Scholar 

  133. Abt ER, Rashid K, Le TM, Li S, Lee HR, Lok V, Li L, Creech AL et al (2022) Purine nucleoside phosphorylase enables dual metabolic checkpoints that prevent T cell immunodeficiency and TLR7-associated autoimmunity. J Clin Investig 132(16). https://doi.org/10.1172/jci160852

  134. Al-Saud B, Al Alawi Z, Hussain FB, Hershfield M, Alkuraya FS, Al-Mayouf SM (2020) A case with purine nucleoside phosphorylase deficiency suffering from late-onset systemic lupus erythematosus and lymphoma. J Clin Immunol 40(6):833–839. https://doi.org/10.1007/s10875-020-00800-y

    Article  CAS  PubMed  Google Scholar 

  135. Markert ML (1991) Purine nucleoside phosphorylase deficiency. Immunodefic Rev 3(1):45–81

    CAS  PubMed  Google Scholar 

  136. Ho MC, Shi W, Rinaldo-Matthis A, Tyler PC, Evans GB, Clinch K, Almo SC, Schramm VL (2010) Four generations of transition-state analogues for human purine nucleoside phosphorylase. Proc Natl Acad Sci USA 107(11):4805–4812. https://doi.org/10.1073/pnas.0913439107

    Article  PubMed  PubMed Central  Google Scholar 

  137. Bortolotti M, Polito L, Battelli MG, Bolognesi A (2021) Xanthine oxidoreductase: one enzyme for multiple physiological tasks. Redox Biol 41:101882. https://doi.org/10.1016/j.redox.2021.101882

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Johnson RJ, Lanaspa MA, Gaucher EA (2011) Uric acid: a danger signal from the RNA world that may have a role in the epidemic of obesity, metabolic syndrome, and cardiorenal disease: evolutionary considerations. Semin Nephrol 31(5):394–399. https://doi.org/10.1016/j.semnephrol.2011.08.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  139. Harrison R (2002) Structure and function of xanthine oxidoreductase: where are we now? Free Radic Biol Med 33(6):774–797. https://doi.org/10.1016/s0891-5849(02)00956-5

    Article  CAS  PubMed  Google Scholar 

  140. Furuhashi M (2020) New insights into purine metabolism in metabolic diseases: role of xanthine oxidoreductase activity. Am J Physiol Endocrinol Metab 319(5):E827-e834. https://doi.org/10.1152/ajpendo.00378.2020

    Article  CAS  PubMed  Google Scholar 

  141. Hille R, Hall J, Basu P (2014) The mononuclear molybdenum enzymes. Chem Rev 114(7):3963–4038. https://doi.org/10.1021/cr400443z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Markley HG, Faillace LA, Mezey E (1973) Xanthine oxidase activity in rat brain. Biochem Biophys Acta 309(1):23–31. https://doi.org/10.1016/0005-2744(73)90313-6

    Article  CAS  PubMed  Google Scholar 

  143. Honorat JA, Kinoshita M, Okuno T, Takata K, Koda T, Tada S, Shirakura T, Fujimura H et al (2013) Xanthine oxidase mediates axonal and myelin loss in a murine model of multiple sclerosis. PLoS ONE 8(8):e71329. https://doi.org/10.1371/journal.pone.0071329

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Rouquette M, Page S, Bryant R, Benboubetra M, Stevens CR, Blake DR, Whish WD, Harrison R et al (1998) Xanthine oxidoreductase is asymmetrically localised on the outer surface of human endothelial and epithelial cells in culture. FEBS Lett 426(3):397–401. https://doi.org/10.1016/s0014-5793(98)00385-8

    Article  CAS  PubMed  Google Scholar 

  145. Burnstock G (2004) Introduction: P2 receptors. Curr Top Med Chem 4(8):793–803. https://doi.org/10.2174/1568026043451014

    Article  CAS  PubMed  Google Scholar 

  146. Egan TM, Samways DSK, Li Z (2006) Biophysics of P2X receptors. Pflugers Arch 452(5):501–512. https://doi.org/10.1007/s00424-006-0078-1

    Article  CAS  PubMed  Google Scholar 

  147. Kaczmarek-Hájek K, Lörinczi E, Hausmann R, Nicke A (2012) Molecular and functional properties of P2X receptors–recent progress and persisting challenges. Purinergic Signal 8(3):375–417. https://doi.org/10.1007/s11302-012-9314-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Abbracchio MP, Burnstock G, Boeynaems JM, Barnard EA, Boyer JL, Kennedy C, Knight GE, Fumagalli M et al (2006) International Union of Pharmacology LVIII: update on the P2Y G protein-coupled nucleotide receptors: from molecular mechanisms and pathophysiology to therapy. Pharmacol Rev 58(3):281–341. https://doi.org/10.1124/pr.58.3.3

    Article  CAS  PubMed  Google Scholar 

  149. Abbracchio MP, Burnstock G, Verkhratsky A, Zimmermann H (2009) Purinergic signalling in the nervous system: an overview. Trends Neurosci 32(1):19–29. https://doi.org/10.1016/j.tins.2008.10.001

    Article  CAS  PubMed  Google Scholar 

  150. Di Virgilio F, Schmalzing G, Markwardt F (2018) The elusive P2X7 macropore. Trends Cell Biol 28(5):392–404. https://doi.org/10.1016/j.tcb.2018.01.005

    Article  CAS  PubMed  Google Scholar 

  151. Illes P, Rubini P, Ulrich H, Zhao Y, Tang Y (2020) Regulation of microglial functions by purinergic mechanisms in the healthy and diseased CNS. Cells 9(5). https://doi.org/10.3390/cells9051108

  152. Davalos D, Grutzendler J, Yang G, Kim JV, Zuo Y, Jung S, Littman DR, Dustin ML et al (2005) ATP mediates rapid microglial response to local brain injury in vivo. Nat Neurosci 8(6):752–758. https://doi.org/10.1038/nn1472

    Article  CAS  PubMed  Google Scholar 

  153. Fekete R, Cserép C, Lénárt N, Tóth K, Orsolits B, Martinecz B, Méhes E, Szabó B et al (2018) Microglia control the spread of neurotropic virus infection via P2Y12 signalling and recruit monocytes through P2Y12-independent mechanisms. Acta Neuropathol 136(3):461–482. https://doi.org/10.1007/s00401-018-1885-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Fredholm BB, Irenius E, Kull B, Schulte G (2001) Comparison of the potency of adenosine as an agonist at human adenosine receptors expressed in Chinese hamster ovary cells. Biochem Pharmacol 61(4):443–448. https://doi.org/10.1016/s0006-2952(00)00570-0

    Article  CAS  PubMed  Google Scholar 

  155. Borea PA, Gessi S, Merighi S, Vincenzi F, Varani K (2018) Pharmacology of adenosine receptors: the state of the art. Physiol Rev 98(3):1591–1625. https://doi.org/10.1152/physrev.00049.2017

    Article  CAS  PubMed  Google Scholar 

  156. da Rocha LF, de Oliveira AP, Accetturi BG, de Oliveira MI, Domingos HV, de Almeida CD, de Lima WT, Santos AR (2013) Anti-inflammatory effects of inosine in allergic lung inflammation in mice: evidence for the participation of adenosine A2A and A 3 receptors. Purinergic Signal 9(3):325–336. https://doi.org/10.1007/s11302-013-9351-x

    Article  CAS  Google Scholar 

  157. Vincenzi F, Pasquini S, Borea PA, Varani K (2020) Targeting adenosine receptors: a potential pharmacological avenue for acute and chronic pain. Int J Mol Sci 21(22):8710

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Jacobson KA, Gao ZG (2006) Adenosine receptors as therapeutic targets. Nat Rev Drug Disc 5(3):247–264. https://doi.org/10.1038/nrd1983

    Article  CAS  Google Scholar 

  159. Beamer E, Gölöncsér F, Horváth G, Bekő K, Otrokocsi L, Koványi B, Sperlágh B (2016) Purinergic mechanisms in neuroinflammation: an update from molecules to behavior. Neuropharmacology 104:94–104. https://doi.org/10.1016/j.neuropharm.2015.09.019

    Article  CAS  PubMed  Google Scholar 

  160. Haskó G, Linden J, Cronstein B, Pacher P (2008) Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat Rev Drug Disc 7(9):759–770. https://doi.org/10.1038/nrd2638

    Article  CAS  Google Scholar 

  161. Duarte-Silva E, Ulrich H, Oliveira-Giacomelli Á, Hartung HP, Meuth SG, Peixoto CA (2022) The adenosinergic signaling in the pathogenesis and treatment of multiple sclerosis. Front Immunol 13:946698. https://doi.org/10.3389/fimmu.2022.946698

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Mills JH, Kim DG, Krenz A, Chen JF, Bynoe MS (2012) A2A adenosine receptor signaling in lymphocytes and the central nervous system regulates inflammation during experimental autoimmune encephalomyelitis. J Immunol (Baltimore, Md: 1950) 188(11):5713–5722. https://doi.org/10.4049/jimmunol.1200545

    Article  CAS  Google Scholar 

  163. Tsutsui S, Schnermann J, Noorbakhsh F, Henry S, Yong VW, Winston BW, Warren K, Power C (2004) A1 adenosine receptor upregulation and activation attenuates neuroinflammation and demyelination in a model of multiple sclerosis. J Neurosci 24(6):1521–1529. https://doi.org/10.1523/jneurosci.4271-03.2004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  164. Filippi M, Bar-Or A, Piehl F, Preziosa P, Solari A, Vukusic S, Rocca MA (2018) Multiple sclerosis. Nat Rev Dis Prim 4(1):43. https://doi.org/10.1038/s41572-018-0041-4

    Article  PubMed  Google Scholar 

  165. McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8(9):913–919. https://doi.org/10.1038/ni1507

    Article  CAS  PubMed  Google Scholar 

  166. Compston A, Coles A (2008) Multiple sclerosis. Lancet (London, England) 372(9648):1502–1517. https://doi.org/10.1016/s0140-6736(08)61620-7

    Article  CAS  PubMed  Google Scholar 

  167. Ziemssen T, Bhan V, Chataway J, Chitnis T, Campbell Cree BA, Havrdova EK, Kappos L, Labauge P et al. (2023) Secondary progressive multiple sclerosis: a review of clinical characteristics, definition, prognostic tools, and disease-modifying therapies. Neurol (R) Neuroimmunol Neuroinflammation 10(1). https://doi.org/10.1212/nxi.0000000000200064

  168. Cree BAC, Arnold DL, Chataway J, Chitnis T, Fox RJ, Pozo Ramajo A, Murphy N, Lassmann H (2021) Secondary progressive multiple sclerosis: new insights. Neurology 97(8):378–388. https://doi.org/10.1212/wnl.0000000000012323

    Article  PubMed  PubMed Central  Google Scholar 

  169. Ontaneda D, Fox RJ (2015) Progressive multiple sclerosis. Curr Opin Neurol 28(3):237–243. https://doi.org/10.1097/wco.0000000000000195

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Bjelobaba I, Begovic-Kupresanin V, Pekovic S, Lavrnja I (2018) Animal models of multiple sclerosis: focus on experimental autoimmune encephalomyelitis. J Neurosci Res 96(6):1021–1042. https://doi.org/10.1002/jnr.24224

    Article  CAS  PubMed  Google Scholar 

  171. Constantinescu CS, Farooqi N, O’Brien K, Gran B (2011) Experimental autoimmune encephalomyelitis (EAE) as a model for multiple sclerosis (MS). Br J Pharmacol 164(4):1079–1106. https://doi.org/10.1111/j.1476-5381.2011.01302.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Sato F, Omura S, Jaffe SL, Tsunoda I (2016) Role of CD4+ T Cells in the pathophysiology of multiple sclerosis. In: Minagar A (ed) Multiple sclerosis: a mechanistic view. Academic Press, pp 41–69

  173. Chitnis T (2007) The role of CD4 T cells in the pathogenesis of multiple sclerosis. Int Rev Neurobiol 79:43–72. https://doi.org/10.1016/s0074-7742(07)79003-7

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Mapunda JA, Tibar H, Regragui W, Engelhardt B (2022) How does the immune system enter the brain? Front Immunol 13:805657. https://doi.org/10.3389/fimmu.2022.805657

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Lassmann H (2018) Multiple Sclerosis Pathology. Cold Spring Harb Perspect Med 8(3). https://doi.org/10.1101/cshperspect.a028936

  176. Tzartos JS, Friese MA, Craner MJ, Palace J, Newcombe J, Esiri MM, Fugger L (2008) Interleukin-17 production in central nervous system-infiltrating T cells and glial cells is associated with active disease in multiple sclerosis. Am J Pathol 172(1):146–155. https://doi.org/10.2353/ajpath.2008.070690

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Goverman JM (2021) Regulatory T Cells in multiple sclerosis. N Engl J Med 384(6):578–580. https://doi.org/10.1056/NEJMcibr2033544

    Article  CAS  PubMed  Google Scholar 

  178. Sojka DK, Huang YH, Fowell DJ (2008) Mechanisms of regulatory T-cell suppression - a diverse arsenal for a moving target. Immunology 124(1):13–22. https://doi.org/10.1111/j.1365-2567.2008.02813.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Zozulya AL, Wiendl H (2008) The role of regulatory T cells in multiple sclerosis. Nat Clin Pract Neurol 4(7):384–398. https://doi.org/10.1038/ncpneuro0832

    Article  CAS  PubMed  Google Scholar 

  180. Rodi M, Dimisianos N, de Lastic AL, Sakellaraki P, Deraos G, Matsoukas J, Papathanasopoulos P, Mouzaki A (2016) Regulatory cell populations in relapsing-remitting multiple sclerosis (RRMS) patients: effect of disease activity and treatment regimens. Int J Mol Sci 17(9). https://doi.org/10.3390/ijms17091398

  181. Putheti P, Pettersson A, Soderstrom M, Link H, Huang YM (2004) Circulating CD4+CD25+ T regulatory cells are not altered in multiple sclerosis and unaffected by disease-modulating drugs. J Clin Immunol 24(2):155–161. https://doi.org/10.1023/b:joci.0000019780.93817.82

    Article  CAS  PubMed  Google Scholar 

  182. Feger U, Luther C, Poeschel S, Melms A, Tolosa E, Wiendl H (2007) Increased frequency of CD4+ CD25+ regulatory T cells in the cerebrospinal fluid but not in the blood of multiple sclerosis patients. Clin Exp Immunol 147(3):412–418. https://doi.org/10.1111/j.1365-2249.2006.03271.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Akirav EM, Bergman CM, Hill M, Ruddle NH (2009) Depletion of CD4(+)CD25(+) T cells exacerbates experimental autoimmune encephalomyelitis induced by mouse, but not rat, antigens. J Neurosci Res 87(15):3511–3519. https://doi.org/10.1002/jnr.21981

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Kohm AP, McMahon JS, Podojil JR, Begolka WS, DeGutes M, Kasprowicz DJ, Ziegler SF, Miller SD (2006) Cutting edge: anti-CD25 monoclonal antibody injection results in the functional inactivation, not depletion, of CD4+CD25+ T regulatory cells. J Immunol (Baltimore, Md: 1950) 176(6):3301–3305. https://doi.org/10.4049/jimmunol.176.6.3301

    Article  CAS  Google Scholar 

  185. Antonioli L, Pacher P, Vizi ES, Haskó G (2013) CD39 and CD73 in immunity and inflammation. Trends Mol Med 19(6):355–367. https://doi.org/10.1016/j.molmed.2013.03.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  186. Yegutkin GG, Henttinen T, Samburski SS, Spychala J, Jalkanen S (2002) The evidence for two opposite, ATP-generating and ATP-consuming, extracellular pathways on endothelial and lymphoid cells. Biochem J 367(Pt 1):121–128. https://doi.org/10.1042/bj20020439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Mandapathil M, Lang S, Gorelik E, Whiteside TL (2009) Isolation of functional human regulatory T cells (Treg) from the peripheral blood based on the CD39 expression. J Immunol Methods 346(1–2):55–63. https://doi.org/10.1016/j.jim.2009.05.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Hauser SL, Bar-Or A, Comi G, Giovannoni G, Hartung HP, Hemmer B, Lublin F, Montalban X et al (2017) Ocrelizumab versus Interferon Beta-1a in relapsing multiple sclerosis. N Engl J Med 376(3):221–234. https://doi.org/10.1056/NEJMoa1601277

    Article  CAS  PubMed  Google Scholar 

  189. Chu F, Shi M, Zheng C, Shen D, Zhu J, Zheng X, Cui L (2018) The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. J Neuroimmunol 318:1–7. https://doi.org/10.1016/j.jneuroim.2018.02.015

    Article  CAS  PubMed  Google Scholar 

  190. Jiang Z, Jiang JX, Zhang GX (2014) Macrophages: a double-edged sword in experimental autoimmune encephalomyelitis. Immunol Lett 160(1):17–22. https://doi.org/10.1016/j.imlet.2014.03.006

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Spiteri AG, Wishart CL, Pamphlett R, Locatelli G, King NJC (2022) Microglia and monocytes in inflammatory CNS disease: integrating phenotype and function. Acta Neuropathol 143(2):179–224. https://doi.org/10.1007/s00401-021-02384-2

    Article  CAS  PubMed  Google Scholar 

  192. Paolicelli RC, Sierra A, Stevens B, Tremblay ME, Aguzzi A, Ajami B, Amit I, Audinat E et al (2022) Microglia states and nomenclature: a field at its crossroads. Neuron 110(21):3458–3483. https://doi.org/10.1016/j.neuron.2022.10.020

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Shin T, Ahn M, Matsumoto Y (2012) Mechanism of experimental autoimmune encephalomyelitis in Lewis rats: recent insights from macrophages. Anat Cell Biol 45(3):141–148. https://doi.org/10.5115/acb.2012.45.3.141

    Article  PubMed  PubMed Central  Google Scholar 

  194. Koeniger T, Kuerten S (2017) Splitting the "unsplittable": dissecting resident and infiltrating macrophages in experimental autoimmune encephalomyelitis. Int J Mol Sci 18(10). https://doi.org/10.3390/ijms18102072

  195. Sofroniew MV (2014) Astrogliosis. Cold Spring Harb Perspect Biol 7(2):a020420. https://doi.org/10.1101/cshperspect.a020420

    Article  PubMed  Google Scholar 

  196. Miljković D, Spasojević I (2013) Multiple sclerosis: molecular mechanisms and therapeutic opportunities. Antioxid Redox Signal 19(18):2286–2334. https://doi.org/10.1089/ars.2012.5068

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Falsig J, Pörzgen P, Lund S, Schrattenholz A, Leist M (2006) The inflammatory transcriptome of reactive murine astrocytes and implications for their innate immune function. J Neurochem 96(3):893–907. https://doi.org/10.1111/j.1471-4159.2005.03622.x

    Article  CAS  PubMed  Google Scholar 

  198. Liddelow SA, Guttenplan KA, Clarke LE, Bennett FC, Bohlen CJ, Schirmer L, Bennett ML, Münch AE et al (2017) Neurotoxic reactive astrocytes are induced by activated microglia. Nature 541(7638):481–487. https://doi.org/10.1038/nature21029

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Mayo L, Trauger SA, Blain M, Nadeau M, Patel B, Alvarez JI, Mascanfroni ID, Yeste A et al (2014) Regulation of astrocyte activation by glycolipids drives chronic CNS inflammation. Nat Med 20(10):1147–1156. https://doi.org/10.1038/nm.3681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Yi W, Schlüter D, Wang X (2019) Astrocytes in multiple sclerosis and experimental autoimmune encephalomyelitis: star-shaped cells illuminating the darkness of CNS autoimmunity. Brain Behav Immun 80:10–24. https://doi.org/10.1016/j.bbi.2019.05.029

    Article  CAS  PubMed  Google Scholar 

  201. Prajeeth CK, Kronisch J, Khorooshi R, Knier B, Toft-Hansen H, Gudi V, Floess S, Huehn J et al (2017) Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties. J Neuroinflammation 14(1):204. https://doi.org/10.1186/s12974-017-0978-3

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Chaudhuri AD, Dastgheyb RM, Yoo SW, Trout A, Talbot CC Jr, Hao H, Witwer KW, Haughey NJ (2018) TNFα and IL-1β modify the miRNA cargo of astrocyte shed extracellular vesicles to regulate neurotrophic signaling in neurons. Cell Death Dis 9(3):363. https://doi.org/10.1038/s41419-018-0369-4

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Pajarillo E, Rizor A, Lee J, Aschner M, Lee E (2019) The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: potential targets for neurotherapeutics. Neuropharmacology 161:107559. https://doi.org/10.1016/j.neuropharm.2019.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Vallejo-Illarramendi A, Domercq M, Pérez-Cerdá F, Ravid R, Matute C (2006) Increased expression and function of glutamate transporters in multiple sclerosis. Neurobiol Dis 21(1):154–164. https://doi.org/10.1016/j.nbd.2005.06.017

    Article  CAS  PubMed  Google Scholar 

  205. Lopes Pinheiro MA, Kooij G, Mizee MR, Kamermans A, Enzmann G, Lyck R, Schwaninger M, Engelhardt B et al (2016) Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim Biophys Acta (BBA) - Mol Basis Dis 1862(3):461–471. https://doi.org/10.1016/j.bbadis.2015.10.018

    Article  CAS  Google Scholar 

  206. Junqueira SC, Dos Santos CI, Lieberknecht V, Cunha MP, Calixto JB, Rodrigues ALS, Santos ARS, Dutra RC (2017) Inosine, an endogenous purine nucleoside, suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis: a role for A2A adenosine receptor. Mol Neurobiol 54(5):3271–3285. https://doi.org/10.1007/s12035-016-9893-3

    Article  CAS  PubMed  Google Scholar 

  207. Zahoor I, Suhail H, Datta I, Ahmed ME, Poisson LM, Waters J, Rashid F, Bin R et al (2022) Blood-based untargeted metabolomics in relapsing-remitting multiple sclerosis revealed the testable therapeutic target. Proc Natl Acad Sci USA 119(25):e2123265119. https://doi.org/10.1073/pnas.2123265119

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Barcelos IP, Troxell RM, Graves JS (2019) Mitochondrial dysfunction and multiple sclerosis. Biology 8(2). https://doi.org/10.3390/biology8020037

  209. Lazzarino G, Amorini AM, Eikelenboom MJ, Killestein J, Belli A, Di Pietro V, Tavazzi B, Barkhof F et al (2010) Cerebrospinal fluid ATP metabolites in multiple sclerosis. Mult Scler (Houndmills, Basingstoke, England) 16(5):549–554. https://doi.org/10.1177/1352458510364196

    Article  CAS  Google Scholar 

  210. Polachini CR, Spanevello RM, Casali EA, Zanini D, Pereira LB, Martins CC, Baldissareli J, Cardoso AM et al (2014) Alterations in the cholinesterase and adenosine deaminase activities and inflammation biomarker levels in patients with multiple sclerosis. Neuroscience 266:266–274. https://doi.org/10.1016/j.neuroscience.2014.01.048

    Article  CAS  PubMed  Google Scholar 

  211. Amorini AM, Petzold A, Tavazzi B, Eikelenboom J, Keir G, Belli A, Giovannoni G, Di Pietro V et al (2009) Increase of uric acid and purine compounds in biological fluids of multiple sclerosis patients. Clin Biochem 42(10–11):1001–1006. https://doi.org/10.1016/j.clinbiochem.2009.03.020

    Article  CAS  PubMed  Google Scholar 

  212. Kuračka L, Kalnovičová T, Kucharská J, Turčáni P (2014) Multiple sclerosis: evaluation of purine nucleotide metabolism in central nervous system in association with serum levels of selected fat-soluble antioxidants. Mult Scler Int 2014:759808. https://doi.org/10.1155/2014/759808

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Tavazzi B, Batocchi AP, Amorini AM, Nociti V, D’Urso S, Longo S, Gullotta S, Picardi M et al (2011) Serum metabolic profile in multiple sclerosis patients. Mult Scler Int 2011:167156. https://doi.org/10.1155/2011/167156

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Drulović J, Dujmović I, Stojsavljević N, Mesaros S, Andjelković S, Miljković D, Perić V, Dragutinović G et al (2001) Uric acid levels in sera from patients with multiple sclerosis. J Neurol 248(2):121–126. https://doi.org/10.1007/s004150170246

    Article  PubMed  Google Scholar 

  215. Peng F, Zhang B, Zhong X, Li J, Xu G, Hu X, Qiu W, Pei Z (2008) Serum uric acid levels of patients with multiple sclerosis and other neurological diseases. Mult Scler (Houndmills, Basingstoke, England) 14(2):188–196. https://doi.org/10.1177/1352458507082143

    Article  CAS  Google Scholar 

  216. Rentzos M, Nikolaou C, Anagnostouli M, Rombos A, Tsakanikas K, Economou M, Dimitrakopoulos A, Karouli M et al (2006) Serum uric acid and multiple sclerosis. Clin Neurol Neurosurg 108(6):527–531. https://doi.org/10.1016/j.clineuro.2005.08.004

    Article  CAS  PubMed  Google Scholar 

  217. Massa J, O’Reilly E, Munger KL, Delorenze GN, Ascherio A (2009) Serum uric acid and risk of multiple sclerosis. J Neurol 256(10):1643–1648. https://doi.org/10.1007/s00415-009-5170-y

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Ramsaransing GS, Heersema DJ, De Keyser J (2005) Serum uric acid, dehydroepiandrosterone sulphate, and apolipoprotein E genotype in benign vs. progressive multiple sclerosis. Eur J Neurol 12(7):514–518. https://doi.org/10.1111/j.1468-1331.2005.01009.x

    Article  CAS  PubMed  Google Scholar 

  219. Zoccolella S, Tortorella C, Iaffaldano P, Direnzo V, D’Onghia M, Luciannatelli E, Paolicelli D, Livrea P et al (2012) Low serum urate levels are associated to female gender in multiple sclerosis patients. PLoS ONE 7(7):e40608. https://doi.org/10.1371/journal.pone.0040608

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  220. Singh J, Cerghet M, Poisson LM, Datta I, Labuzek K, Suhail H, Rattan R, Giri S (2019) Urinary and plasma metabolomics identify the distinct metabolic profile of disease state in chronic mouse model of multiple sclerosis. J Neuroimmune Pharmacol 14(2):241–250. https://doi.org/10.1007/s11481-018-9815-4

    Article  CAS  PubMed  Google Scholar 

  221. Harroud A, Richards JB, Baranzini SE (2021) Mendelian randomization study shows no causal effects of serum urate levels on the risk of MS. Neurol (R) Neuroimmunol Neuroinflamm 8(1). https://doi.org/10.1212/nxi.0000000000000920

  222. Niu P-P, Song B, Wang X, Xu Y-M (2020) Serum uric acid level and multiple sclerosis: a Mendelian randomization study. Front Genet 11. https://doi.org/10.3389/fgene.2020.00254

  223. Muls N, Dang HA, Sindic CJ, van Pesch V (2014) Fingolimod increases CD39-expressing regulatory T cells in multiple sclerosis patients. PLoS ONE 9(11):e113025. https://doi.org/10.1371/journal.pone.0113025

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  224. Dalla Libera D, Di Mitri D, Bergami A, Centonze D, Gasperini C, Grasso MG, Galgani S, Martinelli V et al (2011) T regulatory cells are markers of disease activity in multiple sclerosis patients. PLoS ONE 6(6):e21386. https://doi.org/10.1371/journal.pone.0021386

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  225. Spanevello RM, Mazzanti CM, Schmatz R, Thomé G, Bagatini M, Correa M, Rosa C, Stefanello N et al (2010) The activity and expression of NTPDase is altered in lymphocytes of multiple sclerosis patients. Clin Chim Acta 411(3):210–214. https://doi.org/10.1016/j.cca.2009.11.005

    Article  CAS  PubMed  Google Scholar 

  226. Fletcher JM, Lonergan R, Costelloe L, Kinsella K, Moran B, O'Farrelly C, Tubridy N, Mills KH (2009) CD39+Foxp3+ regulatory T cells suppress pathogenic Th17 cells and are impaired in multiple sclerosis. J Immunol (Baltimore, Md: 1950) 183(11):7602–7610. https://doi.org/10.4049/jimmunol.0901881

  227. Murray PJ (2005) The primary mechanism of the IL-10-regulated antiinflammatory response is to selectively inhibit transcription. Proc Natl Acad Sci USA 102(24):8686–8691. https://doi.org/10.1073/pnas.0500419102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  228. Bahrini K, Belghith M, Maghrebi O, Bekir J, Kchaou M, Jeridi C, Amouri R, Hentati F et al (2020) Discriminative expression of CD39 and CD73 in cerebrospinal fluid of patients with multiple sclerosis and neuro-Behçet’s disease. Cytokine 130:155054. https://doi.org/10.1016/j.cyto.2020.155054

    Article  CAS  PubMed  Google Scholar 

  229. Álvarez-Sánchez N, Cruz-Chamorro I, Díaz-Sánchez M, Lardone PJ, Guerrero JM, Carrillo-Vico A (2019) Peripheral CD39-expressing T regulatory cells are increased and associated with relapsing-remitting multiple sclerosis in relapsing patients. Sci Rep 9(1):2302. https://doi.org/10.1038/s41598-019-38897-w

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Peelen E, Damoiseaux J, Smolders J, Knippenberg S, Menheere P, Tervaert JW, Hupperts R, Thewissen M (2011) Th17 expansion in MS patients is counterbalanced by an expanded CD39+ regulatory T cell population during remission but not during relapse. J Neuroimmunol 240–241:97–103. https://doi.org/10.1016/j.jneuroim.2011.09.013

    Article  CAS  PubMed  Google Scholar 

  231. Liao H, Hyman MC, Baek AE, Fukase K, Pinsky DJ (2010) cAMP/CREB-mediated transcriptional regulation of ectonucleoside triphosphate diphosphohydrolase 1 (CD39) expression. J Biol Chem 285(19):14791–14805. https://doi.org/10.1074/jbc.M110.116905

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Burnstock G, Boeynaems JM (2014) Purinergic signalling and immune cells. Purinergic Signal 10(4):529–564. https://doi.org/10.1007/s11302-014-9427-2

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Aksungar FB, Topkaya AE, Yildiz Z, Sahin S, Turk U (2008) Coagulation status and biochemical and inflammatory markers in multiple sclerosis. J Clin Neurosci 15(4):393–397. https://doi.org/10.1016/j.jocn.2007.02.090

    Article  CAS  PubMed  Google Scholar 

  234. Vandenberghe N, Debouverie M, Anxionnat R, Clavelou P, Bouly S, Weber M (2003) Cerebral venous thrombosis in four patients with multiple sclerosis. Eur J Neurol 10(1):63–66. https://doi.org/10.1046/j.1468-1331.2003.00513.x

    Article  CAS  PubMed  Google Scholar 

  235. Lavrnja I, Bjelobaba I, Stojiljkovic M, Pekovic S, Mostarica-Stojkovic M, Stosic-Grujicic S, Nedeljkovic N (2009) Time-course changes in ectonucleotidase activities during experimental autoimmune encephalomyelitis. Neurochem Int 55(4):193–198. https://doi.org/10.1016/j.neuint.2009.02.013

    Article  CAS  PubMed  Google Scholar 

  236. Zanin RF, Braganhol E, Bergamin LS, Campesato LF, Filho AZ, Moreira JC, Morrone FB, Sévigny J et al (2012) Differential macrophage activation alters the expression profile of NTPDase and ecto-5’-nucleotidase. PLoS ONE 7(2):e31205. https://doi.org/10.1371/journal.pone.0031205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Shinozaki Y, Shibata K, Yoshida K, Shigetomi E, Gachet C, Ikenaka K, Tanaka KF, Koizumi S (2017) Transformation of astrocytes to a neuroprotective phenotype by microglia via P2Y(1) receptor downregulation. Cell Rep 19(6):1151–1164. https://doi.org/10.1016/j.celrep.2017.04.047

    Article  CAS  PubMed  Google Scholar 

  238. Traugott U, Reinherz EL, Raine CS (1983) Multiple sclerosis: distribution of T cell subsets within active chronic lesions. Science (New York, NY) 219(4582):308–310. https://doi.org/10.1126/science.6217550

    Article  CAS  Google Scholar 

  239. Koudriavtseva T (2014) Thrombotic processes in multiple sclerosis as manifestation of innate immune activation. Front Neurol 5:119. https://doi.org/10.3389/fneur.2014.00119

    Article  PubMed  PubMed Central  Google Scholar 

  240. Cunha RA (2001) Adenosine as a neuromodulator and as a homeostatic regulator in the nervous system: different roles, different sources and different receptors. Neurochem Int 38(2):107–125. https://doi.org/10.1016/s0197-0186(00)00034-6

    Article  CAS  PubMed  Google Scholar 

  241. Airas L, Niemelä J, Yegutkin G, Jalkanen S (2007) Mechanism of action of IFN-beta in the treatment of multiple sclerosis: a special reference to CD73 and adenosine. Ann N Y Acad Sci 1110:641–648. https://doi.org/10.1196/annals.1423.067

    Article  CAS  PubMed  Google Scholar 

  242. Vivekanandhan S, Soundararajan CC, Tripathi M, Maheshwari MC (2005) Adenosine deaminase and 5’nucleotidase activities in peripheral blood T cells of multiple sclerosis patients. Neurochem Res 30(4):453–456. https://doi.org/10.1007/s11064-005-2680-6

    Article  CAS  PubMed  Google Scholar 

  243. Adzic Bukvic M, Laketa D, Dragic M, Lavrnja I, Nedeljkovic N (2024) Expression of functionally distinct ecto-5’-nucleotidase/CD73 glycovariants in reactive astrocytes in experimental autoimmune encephalomyelitis and neuroinflammatory conditions in vitro. Glia 72(1):19–33. https://doi.org/10.1002/glia.24459

    Article  CAS  PubMed  Google Scholar 

  244. Nedeljkovic N (2019) Complex regulation of ecto-5’-nucleotidase/CD73 and A(2A)R-mediated adenosine signaling at neurovascular unit: a link between acute and chronic neuroinflammation. Pharmacol Res 144:99–115. https://doi.org/10.1016/j.phrs.2019.04.007

    Article  CAS  PubMed  Google Scholar 

  245. Antonioli L, Colucci R, La Motta C, Tuccori M, Awwad O, Da Settimo F, Blandizzi C, Fornai M (2012) Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr Drug Targets 13(6):842–862. https://doi.org/10.2174/138945012800564095

    Article  CAS  PubMed  Google Scholar 

  246. Flinn AM, Gennery AR (2018) Adenosine deaminase deficiency: a review. Orphanet J Rare Dis 13(1):65. https://doi.org/10.1186/s13023-018-0807-5

    Article  PubMed  PubMed Central  Google Scholar 

  247. Spanevello RM, Mazzanti CM, Bagatini M, Correa M, Schmatz R, Stefanello N, Thomé G, Morsch VM et al (2010) Activities of the enzymes that hydrolyze adenine nucleotides in platelets from multiple sclerosis patients. J Neurol 257(1):24–30. https://doi.org/10.1007/s00415-009-5258-4

    Article  CAS  PubMed  Google Scholar 

  248. Samuraki M, Sakai K, Odake Y, Yoshita M, Misaki K, Nakada M, Yamada M (2017) Multiple sclerosis showing elevation of adenosine deaminase levels in the cerebrospinal fluid. Mult Scler Relat Disord 13:44–46. https://doi.org/10.1016/j.msard.2017.02.005

    Article  PubMed  Google Scholar 

  249. Kutryb-Zajac B, Kawecka A, Caratis F, Urbanowicz K, Braczko A, Furihata T, Karaszewski B, Smolenski RT et al (2022) The impaired distribution of adenosine deaminase isoenzymes in multiple sclerosis plasma and cerebrospinal fluid. Front Mol Neurosci 15:998023. https://doi.org/10.3389/fnmol.2022.998023

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Moreno E, Canet J, Gracia E, Lluís C, Mallol J, Canela EI, Cortés A, Casadó V (2018) Molecular Evidence of Adenosine Deaminase Linking Adenosine A(2A) Receptor and CD26 proteins. Front Pharmacol 9:106. https://doi.org/10.3389/fphar.2018.00106

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Kutryb-Zajac B, Harasim G, Jedrzejewska A, Krol O, Braczko A, Jablonska P, Mierzejewska P, Zielinski J et al (2021) Macrophage-derived adenosine deaminase 2 correlates with M2 macrophage phenotype in triple negative breast cancer. Int J Mol Sci 22(7). https://doi.org/10.3390/ijms22073764

  252. Zavialov AV, Gracia E, Glaichenhaus N, Franco R, Zavialov AV, Lauvau G (2010) Human adenosine deaminase 2 induces differentiation of monocytes into macrophages and stimulates proliferation of T helper cells and macrophages. J Leukoc Biol 88(2):279–290. https://doi.org/10.1189/jlb.1109764

    Article  CAS  PubMed  Google Scholar 

  253. Kutryb-Zajac B, Mateuszuk L, Zukowska P, Jasztal A, Zabielska MA, Toczek M, Jablonska P, Zakrzewska A et al (2016) Increased activity of vascular adenosine deaminase in atherosclerosis and therapeutic potential of its inhibition. Cardiovasc Res 112(2):590–605. https://doi.org/10.1093/cvr/cvw203

    Article  CAS  PubMed  Google Scholar 

  254. Stampanoni Bassi M, Buttari F, Simonelli I, Gilio L, Furlan R, Finardi A, Marfia GA, Visconti A et al. (2020) A single nucleotide ADA genetic variant is associated to central inflammation and clinical presentation in MS: implications for cladribine treatment. Genes 11(10). https://doi.org/10.3390/genes11101152

  255. Hanna AN, Waldman WJ, Lott JA, Koesters SC, Hughes AM, Thornton DJ (1997) Increased alkaline phosphatase isoforms in autoimmune diseases. Clin Chem 43(8 Pt 1):1357–1364

    Article  CAS  PubMed  Google Scholar 

  256. Huizinga R, Kreft KL, Onderwater S, Boonstra JG, Brands R, Hintzen RQ, Laman JD (2012) Endotoxin- and ATP-neutralizing activity of alkaline phosphatase as a strategy to limit neuroinflammation. J Neuroinflammation 9(1):266. https://doi.org/10.1186/1742-2094-9-266

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Hammack BN, Fung KY, Hunsucker SW, Duncan MW, Burgoon MP, Owens GP, Gilden DH (2004) Proteomic analysis of multiple sclerosis cerebrospinal fluid. Mult Scler (Houndmills, Basingstoke, England) 10(3):245–260. https://doi.org/10.1191/1352458504ms1023oa

    Article  CAS  Google Scholar 

  258. Giuliani P, Zuccarini M, Buccella S, Peña-Altamira LE, Polazzi E, Virgili M, Monti B, Poli A et al (2017) Evidence for purine nucleoside phosphorylase (PNP) release from rat C6 glioma cells. J Neurochem 141(2):208–221. https://doi.org/10.1111/jnc.14004

    Article  CAS  PubMed  Google Scholar 

  259. Peña-Altamira LE, Polazzi E, Giuliani P, Beraudi A, Massenzio F, Mengoni I, Poli A, Zuccarini M et al (2018) Release of soluble and vesicular purine nucleoside phosphorylase from rat astrocytes and microglia induced by pro-inflammatory stimulation with extracellular ATP via P2X(7) receptors. Neurochem Int 115:37–49. https://doi.org/10.1016/j.neuint.2017.10.010

    Article  CAS  PubMed  Google Scholar 

  260. Silva RG, Santos DS, Basso LA, Oses JP, Wofchuk S, Portela LV, Souza DO (2004) Purine nucleoside phosphorylase activity in rat cerebrospinal fluid. Neurochem Res 29(10):1831–1835. https://doi.org/10.1023/b:nere.0000042209.02324.98

    Article  PubMed  Google Scholar 

  261. Honorat JA, Nakatsuji Y, Shimizu M, Kinoshita M, Sumi-Akamaru H, Sasaki T, Takata K, Koda T (2017) Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner. PLoS ONE 12(11):e0187215. https://doi.org/10.1371/journal.pone.0187215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Nomura J, Busso N, Ives A, Matsui C, Tsujimoto S, Shirakura T, Tamura M, Kobayashi T et al (2014) Xanthine oxidase inhibition by febuxostat attenuates experimental atherosclerosis in mice. Sci Rep 4(1):4554. https://doi.org/10.1038/srep04554

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Beaino W, Janssen B, Kooij G, van der Pol SMA, van Het Hof B, van Horssen J, Windhorst AD, de Vries HE (2017) Purinergic receptors P2Y12R and P2X7R: potential targets for PET imaging of microglia phenotypes in multiple sclerosis. J Neuroinflammation 14(1):259. https://doi.org/10.1186/s12974-017-1034-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Grygorowicz T, Strużyńska L (2019) Early P2X7R-dependent activation of microglia during the asymptomatic phase of autoimmune encephalomyelitis. Inflammopharmacology 27(1):129–137. https://doi.org/10.1007/s10787-018-0528-3

    Article  CAS  PubMed  Google Scholar 

  265. Gu BJ, Wiley JS (2018) P2X7 as a scavenger receptor for innate phagocytosis in the brain. Br J Pharmacol 175(22):4195–4208. https://doi.org/10.1111/bph.14470

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Matute C, Torre I, Pérez-Cerdá F, Pérez-Samartín A, Alberdi E, Etxebarria E, Arranz AM, Ravid R et al (2007) P2X(7) receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates experimental autoimmune encephalomyelitis. J Neurosci 27(35):9525–9533. https://doi.org/10.1523/jneurosci.0579-07.2007

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  267. Yiangou Y, Facer P, Durrenberger P, Chessell IP, Naylor A, Bountra C, Banati RR, Anand P (2006) COX-2, CB2 and P2X7-immunoreactivities are increased in activated microglial cells/macrophages of multiple sclerosis and amyotrophic lateral sclerosis spinal cord. BMC Neurol 6:12. https://doi.org/10.1186/1471-2377-6-12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  268. Guo LH, Schluesener HJ (2005) Lesional accumulation of P2X(4) receptor(+) macrophages in rat CNS during experimental autoimmune encephalomyelitis. Neuroscience 134(1):199–205. https://doi.org/10.1016/j.neuroscience.2005.04.026

    Article  CAS  PubMed  Google Scholar 

  269. Vázquez-Villoldo N, Domercq M, Martín A, Llop J, Gómez-Vallejo V, Matute C (2014) P2X4 receptors control the fate and survival of activated microglia. Glia 62(2):171–184. https://doi.org/10.1002/glia.22596

    Article  PubMed  Google Scholar 

  270. Zabala A, Vazquez-Villoldo N, Rissiek B, Gejo J, Martin A, Palomino A, Perez-Samartín A, Pulagam KR et al (2018) P2X4 receptor controls microglia activation and favors remyelination in autoimmune encephalitis. EMBO Mol Med 10(8):e8743. https://doi.org/10.15252/emmm.201708743

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Ingwersen J, Wingerath B, Graf J, Lepka K, Hofrichter M, Schröter F, Wedekind F, Bauer A et al (2016) Dual roles of the adenosine A2a receptor in autoimmune neuroinflammation. J Neuroinflammation 13:48. https://doi.org/10.1186/s12974-016-0512-z

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Johnston JB, Silva C, Gonzalez G, Holden J, Warren KG, Metz LM, Power C (2001) Diminished adenosine A1 receptor expression on macrophages in brain and blood of patients with multiple sclerosis. Ann Neurol 49(5):650–658

    Article  CAS  PubMed  Google Scholar 

  273. Rissanen E, Virta JR, Paavilainen T, Tuisku J, Helin S, Luoto P, Parkkola R, Rinne JO et al (2013) Adenosine A2A receptors in secondary progressive multiple sclerosis: a [11C]TMSX Brain PET study. J Cereb Blood Flow Metab 33(9):1394–1401. https://doi.org/10.1038/jcbfm.2013.85

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Safarzadeh E, Jadidi-Niaragh F, Motallebnezhad M, Yousefi M (2016) The role of adenosine and adenosine receptors in the immunopathogenesis of multiple sclerosis. Inflamm Res 65(7):511–520. https://doi.org/10.1007/s00011-016-0936-z

    Article  CAS  PubMed  Google Scholar 

  275. Yao SQ, Li ZZ, Huang QY, Li F, Wang ZW, Augusto E, He JC, Wang XT et al (2012) Genetic inactivation of the adenosine A(2A) receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis. J Neurochem 123(1):100–112. https://doi.org/10.1111/j.1471-4159.2012.07807.x

    Article  CAS  PubMed  Google Scholar 

  276. Qin C, Zhou J, Gao Y, Lai W, Yang C, Cai Y, Chen S, Du C (2017) Critical role of P2Y(12) receptor in regulation of Th17 differentiation and experimental autoimmune encephalomyelitis pathogenesis. J Immunol (Baltimore, Md: 1950) 199(1):72–81. https://doi.org/10.4049/jimmunol.1601549

    Article  CAS  Google Scholar 

  277. Amadio S, Parisi C, Piras E, Fabbrizio P, Apolloni S, Montilli C, Luchetti S, Ruggieri S et al (2017) Modulation of P2X7 receptor during inflammation in multiple sclerosis. Front Immunol 8:1529. https://doi.org/10.3389/fimmu.2017.01529

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Domercq M, Matute C (2019) Targeting P2X4 and P2X7 receptors in multiple sclerosis. Curr Opin Pharmacol 47:119–125. https://doi.org/10.1016/j.coph.2019.03.010

    Article  CAS  PubMed  Google Scholar 

  279. Miras-Portugal MT, Sebastián-Serrano Á, García LdD, Díaz-Hernández M (2017) Neuronal P2X7 receptor: involvement in neuronal physiology and pathology. J Neurosci 37(30):7063–7072. https://doi.org/10.1523/jneurosci.3104-16.2017

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Di Virgilio F (2007) Liaisons dangereuses: P2X(7) and the inflammasome. Trends Pharmacol Sci 28(9):465–472. https://doi.org/10.1016/j.tips.2007.07.002

    Article  CAS  PubMed  Google Scholar 

  281. Matute C, Cavaliere F (2011) Neuroglial interactions mediated by purinergic signalling in the pathophysiology of CNS disorders. Semin Cell Dev Biol 22(2):252–259. https://doi.org/10.1016/j.semcdb.2011.02.011

    Article  CAS  PubMed  Google Scholar 

  282. Chen L, Brosnan CF (2006) Regulation of immune response by P2X7 receptor. Crit Rev Immunol 26(6):499–513. https://doi.org/10.1615/critrevimmunol.v26.i6.30

    Article  CAS  PubMed  Google Scholar 

  283. Zhang J, Li Z, Hu X, Su Q, He C, Liu J, Ren H, Qian M et al (2017) Knockout of P2Y12 aggravates experimental autoimmune encephalomyelitis in mice via increasing of IL-23 production and Th17 cell differentiation by dendritic cells. Brain Behav Immun 62:245–255. https://doi.org/10.1016/j.bbi.2016.12.001

    Article  CAS  PubMed  Google Scholar 

  284. Amadio S, Montilli C, Magliozzi R, Bernardi G, Reynolds R, Volonté C (2010) P2Y12 receptor protein in cortical gray matter lesions in multiple sclerosis. Cereb Cortex (New York, NY: 1991) 20(6):1263–1273. https://doi.org/10.1093/cercor/bhp193

    Article  Google Scholar 

  285. Sasaki Y, Hoshi M, Akazawa C, Nakamura Y, Tsuzuki H, Inoue K, Kohsaka S (2003) Selective expression of Gi/o-coupled ATP receptor P2Y12 in microglia in rat brain. Glia 44(3):242–250. https://doi.org/10.1002/glia.10293

    Article  PubMed  Google Scholar 

  286. Antonioli L, Blandizzi C, Pacher P, Haskó G (2019) The purinergic system as a pharmacological target for the treatment of immune-mediated inflammatory diseases. Pharmacol Rev 71(3):345–382. https://doi.org/10.1124/pr.117.014878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  287. Cellai L, Carvalho K, Faivre E, Deleau A, Vieau D, Buée L, Blum D, Mériaux C et al. (2018) The adenosinergic signaling: a complex but promising therapeutic target for Alzheimer’s disease. Front Neurosci 12. https://doi.org/10.3389/fnins.2018.00520

  288. Faivre E, Coelho JE, Zornbach K, Malik E, Baqi Y, Schneider M, Cellai L, Carvalho K et al (2018) Beneficial effect of a selective adenosine A(2A) receptor antagonist in the APPswe/PS1dE9 mouse model of Alzheimer’s disease. Front Mol Neurosci 11:235. https://doi.org/10.3389/fnmol.2018.00235

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Colella M, Zinni M, Pansiot J, Cassanello M, Mairesse J, Ramenghi L, Baud O (2018) Modulation of microglial activation by adenosine A2a receptor in animal models of perinatal brain injury. Front Neurol 9. https://doi.org/10.3389/fneur.2018.00605

  290. Wei W, Du C, Lv J, Zhao G, Li Z, Wu Z, Haskó G, Xie X (2013) Blocking A2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation. J Immunol (Baltimore, Md: 1950) 190(1):138–146. https://doi.org/10.4049/jimmunol.1103721

    Article  CAS  Google Scholar 

  291. Varani K, Maniero S, Vincenzi F, Targa M, Stefanelli A, Maniscalco P, Martini F, Tognon M et al (2011) A3 receptors are overexpressed in pleura from patients with mesothelioma and reduce cell growth via Akt/nuclear factor-κB pathway. Am J Respir Crit Care Med 183(4):522–530. https://doi.org/10.1164/rccm.201006-0980OC

    Article  CAS  PubMed  Google Scholar 

  292. Lee JY, Jhun BS, Oh YT, Lee JH, Choe W, Baik HH, Ha J, Yoon KS et al (2006) Activation of adenosine A3 receptor suppresses lipopolysaccharide-induced TNF-alpha production through inhibition of PI 3-kinase/Akt and NF-kappaB activation in murine BV2 microglial cells. Neurosci Lett 396(1):1–6. https://doi.org/10.1016/j.neulet.2005.11.004

    Article  CAS  PubMed  Google Scholar 

  293. Fredholm BB (2010) Adenosine receptors as drug targets. Exp Cell Res 316(8):1284–1288. https://doi.org/10.1016/j.yexcr.2010.02.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Rodrigues RJ, Figueira AS, Marques JM (2022) P2Y1 Receptor as a catalyst of brain neurodegeneration. NeuroSci 3(4):604–615

    Article  Google Scholar 

  295. Pérez-Sen R, Queipo MJ, Morente V, Ortega F, Delicado EG, Miras-Portugal MT (2015) Neuroprotection mediated by P2Y13 nucleotide receptors in neurons. Comput Struct Biotechnol J 13:160–168. https://doi.org/10.1016/j.csbj.2015.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  296. Welihinda AA, Kaur M, Greene K, Zhai Y, Amento EP (2016) The adenosine metabolite inosine is a functional agonist of the adenosine A2A receptor with a unique signaling bias. Cell Signal 28(6):552–560. https://doi.org/10.1016/j.cellsig.2016.02.010

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Prof. Nadežda Nedeljković for valuable discussion on the topic of this review.

Funding

The authors of this work are supported by grants No. 451–03-47/2023–01/ 200178 and 451–03-47/2023–01/200007 from the Ministry of Science, Technological Development and Innovation of the Republic of Serbia.

Author information

Authors and Affiliations

  1. Department of General Physiology and Biophysics, Institute for Physiology and Biochemistry “Ivan Djaja”, Faculty of Biology, University of Belgrade, Studentski Trg 3, Belgrade, Republic of Serbia

    Danijela Laketa

  2. Institute for Biological Research, Sinisa Stankovic” - National Institute of the Republic of Serbia, University of Belgrade, Bulevar despota Stefana 142, Belgrade, Republic of Serbia

    Irena Lavrnja

Authors
  1. Danijela Laketa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Irena Lavrnja
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

D.L. and I.L. designed the scope of the paper, drafted the manuscript, and provided critical revision of the first draft of the manuscript. D.L and I.L. read and approved the final manuscript.

Corresponding author

Correspondence to Danijela Laketa.

Ethics declarations

Ethics Approval

Not applicable.

Consent to Participate

Not applicable.

Competing Interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Laketa, D., Lavrnja, I. Extracellular Purine Metabolism—Potential Target in Multiple Sclerosis. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04104-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04104-9

Keywords

Search

Navigation