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Secretion of Matrix Metalloproteinase-9 from Astrocytes by Inhibition of Tonic P2Y14-Receptor-Mediated Signal(s)

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Abstract

Glial cells have various important roles in regulation of brain functions. For such events, extracellular nucleotides/P2 receptors have central roles. Although there have been huge amount of literature about activation of P2 receptors and glial functions, little is known about what happens in glia or the brain if glial P2 receptor is inhibited. Here we show that the inhibition of P2 receptors in astrocytes, the most abundant glial cells and cause a constitutive release of nucleotides, resulted in secretion of metalloproteinase-9 (MMP-9), a metal-dependent endopeptidase that degrades extracellular matrix molecules and is important in regulation of brain remodeling. When cultured astrocytes were treated with apyrase (ecto-nucleotidase), reactive blue 2 (P2 receptor antagonist), and pertussis toxin, they secreted MMP-9, suggesting that Gi-coupled P2Y receptor-mediated signals constitutively suppress the production of MMP-9. Among Gi-coupled P2Y receptors, we found that an inhibition of P2Y14 receptor, a receptor for nucleotide-sugars such as UDP-glucose, is responsible for the production of MMP-9 by pharmacological and molecular biochemical analysis. As for the mechanisms, the inhibition of P2Y14 receptors resulted in the release of tumor necrosis factor (TNF)-α which then acted on astrocytes to induce MMP-9. Taken together, our results suggest that the constitutive releases of nucleotide-sugars in astrocytes should play an important role in maintaining the normal status of the cell, through Gi-coupled P2Y14 receptors, and when the signal is removed, the cells start to release TNF-α, which then acts on astrocytes in a feedback fashion to boost MMP-9 synthesis and secretion.

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References

  • Arai K, Lee SR, Lo EH (2003) Essential role for ERK mitogen-activated protein kinase in matrix metalloproteinase-9 regulation in rat cortical astrocytes. Glia 43:254–264

    Article  PubMed  Google Scholar 

  • Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20:1681–1689

    Article  PubMed  CAS  Google Scholar 

  • Asahi M, Wang X, Mori T, Sumii T, Jung JC, Moskowitz MA, Fini ME, Lo EH (2001) Effects of matrix metalloproteinase-9 gene knock-out on the proteolysis of blood–brain barrier and white matter components after cerebral ischemia. J Neurosci 21:7724–7732

    PubMed  CAS  Google Scholar 

  • Backstrom JR, Lim GP, Cullen MJ, Tokes ZA (1996) Matrix metalloproteinase-9 (MMP-9) is synthesized in neurons of the human hippocampus and is capable of degrading the amyloid-beta peptide (1–40). J Neurosci 16:7910–7919

    PubMed  CAS  Google Scholar 

  • Bianco F, Fumagalli M, Pravettoni E, D’Ambrosi N, Volonte C, Matteoli M, Abbracchio MP, Verderio C (2005) Pathophysiological roles of extracellular nucleotides in glial cells: differential expression of purinergic receptors in resting and activated microglia. Brain Res Brain Res Rev 48:144–156

    Article  PubMed  CAS  Google Scholar 

  • Braun N, Zhu Y, Krieglstein J, Culmsee C, Zimmermann H (1998) Upregulation of the enzyme chain hydrolyzing extracellular ATP after transient forebrain ischemia in the rat. J Neurosci 18:4891–4900

    PubMed  CAS  Google Scholar 

  • Brautigam VM, Dubyak GR, Crain JM, Watters JJ (2008) The inflammatory effects of UDP-glucose in N9 microglia are not mediated by P2Y14 receptor activation. Purinergic Signal 4:73–78

    Article  PubMed  CAS  Google Scholar 

  • Chambers JK, Macdonald LE, Sarau HM, Ames RS, Freeman K, Foley JJ, Zhu Y, McLaughlin MM, Murdock P, McMillan L, Trill J, Swift A, Aiyar N, Taylor P, Vawter L, Naheed S, Szekeres P, Hervieu G, Scott C, Watson JM, Murphy AJ, Duzic E, Klein C, Bergsma DJ, Wilson S, Livi GP (2000) A G protein-coupled receptor for UDP-glucose. J Biol Chem 275:10767–10771

    Article  PubMed  CAS  Google Scholar 

  • Cotrina ML, Lin JH, Alves-Rodrigues A, Liu S, Li J, Azmi-Ghadimi H, Kang J, Naus CC, Nedergaard M (1998) Connexins regulate calcium signaling by controlling ATP release. Proc Natl Acad Sci USA 95:15735–15740

    Article  PubMed  CAS  Google Scholar 

  • Cuzner ML, Gveric D, Strand C, Loughlin AJ, Paemen L, Opdenakker G, Newcombe J (1996) The expression of tissue-type plasminogen activator, matrix metalloproteases and endogenous inhibitors in the central nervous system in multiple sclerosis: comparison of stages in lesion evolution. J Neuropathol Exp Neurol 55:1194–1204

    Article  PubMed  CAS  Google Scholar 

  • Deb S, Gottschall PE (1996) Increased production of matrix metalloproteinases in enriched astrocyte and mixed hippocampal cultures treated with beta-amyloid peptides. J Neurochem 66:1641–1647

    Article  PubMed  CAS  Google Scholar 

  • Deb S, Wenjun Zhang J, Gottschall PE (2003) Beta-amyloid induces the production of active, matrix-degrading proteases in cultured rat astrocytes. Brain Res 970:205–213

    Article  PubMed  Google Scholar 

  • Dewil M, Schurmans C, Starckx S, Opdenakker G, Van Den Bosch L, Robberecht W (2005) Role of matrix metalloproteinase-9 in a mouse model for amyotrophic lateral sclerosis. NeuroReport 16:321–324

    Article  PubMed  CAS  Google Scholar 

  • Dovlatova N, Wijeyeratne YD, Fox SC, Manolopoulos P, Johnson AJ, White AE, Latif ML, Ralevic V, Heptinstall S (2008) Detection of P2Y(14) protein in platelets and investigation of the role of P2Y(14) in platelet function in comparison with the EP(3) receptor. Thromb Haemost 100:261–270

    PubMed  CAS  Google Scholar 

  • Dzwonek J, Rylski M, Kaczmarek L (2004) Matrix metalloproteinases and their endogenous inhibitors in neuronal physiology of the adult brain. FEBS Lett 567:129–135

    Article  PubMed  CAS  Google Scholar 

  • Franke H, Verkhratsky A, Burnstock G, Illes P (2012) Pathophysiology of astroglial purinergic signalling. Purinergic Signal 8:629–657

    Article  PubMed  CAS  Google Scholar 

  • Fricks IP, Maddileti S, Carter RL, Lazarowski ER, Nicholas RA, Jacobson KA, Harden TK (2008) UDP is a competitive antagonist at the human P2Y14 receptor. J Pharmacol Exp Ther 325:588–594

    Article  PubMed  CAS  Google Scholar 

  • Fumagalli M, Brambilla R, D'Ambrosi N, Volonté C, Matteoli M, Verderio C, Abbracchio MP (2003) Nucleotide-mediated calcium signaling in rat cortical astrocytes: role of P2X and P2Y receptors. Glia 43:218–230

    Article  PubMed  Google Scholar 

  • Gottschall PE, Deb S (1996) Regulation of matrix metalloproteinase expressions in astrocytes, microglia and neurons. Neuroimmunomodulation 3:69–75

    Article  PubMed  CAS  Google Scholar 

  • Gottschall PE, Yu X (1995) Cytokines regulate gelatinase A and B (matrix metalloproteinase 2 and 9) activity in cultured rat astrocytes. J Neurochem 64:1513–1520

    Article  PubMed  CAS  Google Scholar 

  • Gu Z, Cui J, Brown S, Fridman R, Mobashery S, Strongin AY, Lipton SA (2005) A highly specific inhibitor of matrix metalloproteinase-9 rescues laminin from proteolysis and neurons from apoptosis in transient focal cerebral ischemia. J Neurosci 25:6401–6408

    Article  PubMed  CAS  Google Scholar 

  • Guthrie PB, Knappenberger J, Segal M, Bennett MV, Charles AC, Kater SB (1999) ATP released from astrocytes mediates glial calcium waves. J Neurosci 19:520–528

    PubMed  CAS  Google Scholar 

  • Hayakawa K, Pham LD, Katusic ZS, Arai K, Lo EH (2012) Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc Natl Acad Sci USA 109:7505–7510

    Article  PubMed  CAS  Google Scholar 

  • Haydon PG (2001) GLIA: listening and talking to the synapse. Nat Rev Neurosci 2:185–193

    Article  PubMed  CAS  Google Scholar 

  • Hollopeter G, Jantzen HM, Vincent D, Li G, England L, Ramakrishnan V, Yang RB, Nurden P, Nurden A, Julius D, Conley PB (2001) Identification of the platelet ADP receptor targeted by antithrombotic drugs. Nature 409:202–207

    Article  PubMed  CAS  Google Scholar 

  • Homolya L, Steinberg TH, Boucher RC (2000) Cell to cell communication in response to mechanical stress via bilateral release of ATP and UTP in polarized epithelia. J Cell Biol 150:1349–1360

    Article  PubMed  CAS  Google Scholar 

  • Hsieh HL, Yen MH, Jou MJ, Yang CM (2004) Intracellular signalings underlying bradykinin-induced matrix metalloproteinase-9 expression in rat brain astrocyte-1. Cell Signal 16:1163–1176

    Article  PubMed  CAS  Google Scholar 

  • Hsieh HL, Wang HH, Wu WB, Chu PJ, Yang CM (2010) Transforming growth factor-beta1 induces matrix metalloproteinase-9 and cell migration in astrocytes: roles of ROS-dependent ERK- and JNK-NF-kappaB pathways. J Neuroinflamm 7:88

    Article  CAS  Google Scholar 

  • Jiang X, Namura S, Nagata I (2001) Matrix metalloproteinase inhibitor KB-R7785 attenuates brain damage resulting from permanent focal cerebral ischemia in mice. Neurosci Lett 305:41–44

    Article  PubMed  CAS  Google Scholar 

  • Kaneko N, Marin O, Koike M, Hirota Y, Uchiyama Y, Wu JY, Lu Q, Tessier-Lavigne M, Alvarez-Buylla A, Okano H, Rubenstein JL, Sawamoto K (2010) New neurons clear the path of astrocytic processes for their rapid migration in the adult brain. Neuron 67:213–223

    Article  PubMed  CAS  Google Scholar 

  • Koizumi S, Fujishita K, Tsuda M, Shigemoto-Mogami Y, Inoue K (2003) Dynamic inhibition of excitatory synaptic transmission by astrocyte-derived ATP in hippocampal cultures. Proc Natl Acad Sci USA 100:11023–11028

    Article  PubMed  CAS  Google Scholar 

  • Lazarowski ER, Homolya L, Boucher RC, Harden TK (1997) Direct demonstration of mechanically induced release of cellular UTP and its implication for uridine nucleotide receptor activation. J Biol Chem 272:24348–24354

    Article  PubMed  CAS  Google Scholar 

  • 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 275:31061–31068

    Article  PubMed  CAS  Google Scholar 

  • Lazarowski ER, Boucher RC, Harden TK (2003a) Mechanisms of release of nucleotides and integration of their action as P2X- and P2Y-receptor activating molecules. Mol Pharmacol 64:785–795

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  • Lee WJ, Shin CY, Yoo BK, Ryu JR, Choi EY, Cheong JH, Ryu JH, Ko KH (2003) Induction of matrix metalloproteinase-9 (MMP-9) in lipopolysaccharide-stimulated primary astrocytes is mediated by extracellular signal-regulated protein kinase 1/2 (Erk1/2). Glia 41:15–24

    Article  PubMed  Google Scholar 

  • Lee SR, Kim HY, Rogowska J, Zhao BQ, Bhide P, Parent JM, Lo EH (2006) Involvement of matrix metalloproteinase in neuroblast cell migration from the subventricular zone after stroke. J Neurosci 26:3491–3495

    Article  PubMed  CAS  Google Scholar 

  • Lelongt B, Bengatta S, Delauche M, Lund LR, Werb Z, Ronco PM (2001) Matrix metalloproteinase 9 protects mice from anti-glomerular basement membrane nephritis through its fibrinolytic activity. J Exp Med 193:793–802

    Article  PubMed  CAS  Google Scholar 

  • Leveque T, Le Pavec G, Boutet A, Tardieu M, Dormont D, Gras G (2004) Differential regulation of gelatinase A and B and TIMP-1 and -2 by TNFalpha and HIV virions in astrocytes. Microbes Infect 6:157–163

    Article  PubMed  CAS  Google Scholar 

  • Liu K, Wahlberg P, Ny T (1998) Coordinated and cell-specific regulation of membrane type matrix metalloproteinase 1 (MT1-MMP) and its substrate matrix metalloproteinase 2 (MMP-2) by physiological signals during follicular development and ovulation. Endocrinology 139:4735–4738

    Article  PubMed  CAS  Google Scholar 

  • Lu L, Tonchev AB, Kaplamadzhiev DB, Boneva NB, Mori Y, Sahara S, Ma D, Nakaya MA, Kikuchi M, Yamashima T (2008) Expression of matrix metalloproteinases in the neurogenic niche of the adult monkey hippocampus after ischemia. Hippocampus 18:1074–1084

    Article  PubMed  CAS  Google Scholar 

  • Marteau F, Le Poul E, Communi D, Communi D, Labouret C, Savi P, Boeynaems JM, Gonzalez NS (2003) Pharmacological characterization of the human P2Y13 receptor. Mol Pharmacol 64:104–112

    Article  PubMed  CAS  Google Scholar 

  • Moore DJ, Murdock PR, Watson JM, Faull RL, Waldvogel HJ, Szekeres PG, Wilson S, Freeman KB, Emson PC (2003) GPR105, a novel Gi/o-coupled UDP-glucose receptor expressed on brain glia and peripheral immune cells, is regulated by immunologic challenge: possible role in neuroimmune function. Brain Res Mol Brain Res 118:10–23

    Article  PubMed  CAS  Google Scholar 

  • Mun-Bryce S, Rosenberg GA (1998) Matrix metalloproteinases in cerebrovascular disease. J Cereb Blood Flow Metab 18:1163–1172

    Article  PubMed  CAS  Google Scholar 

  • Murata Y, Fujiwara N, Seo JH, Yan F, Liu X, Terasaki Y, Luo Y, Arai K, Ji X, Lo EH (2012) Delayed inhibition of c-Jun N-terminal kinase worsens outcomes after focal cerebral ischemia. J Neurosci 32:8112–8115

    Article  PubMed  CAS  Google Scholar 

  • Nagase H, Woessner JF Jr (1999) Matrix metalloproteinases. J Biol Chem 274:21491–21494

    Article  PubMed  CAS  Google Scholar 

  • Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530

    Article  PubMed  CAS  Google Scholar 

  • Newman EA (2003) New roles for astrocytes: regulation of synaptic transmission. Trends Neurosci 26:536–542

    Article  PubMed  CAS  Google Scholar 

  • Noble LJ, Donovan F, Igarashi T, Goussev S, Werb Z (2002) Matrix metalloproteinases limit functional recovery after spinal cord injury by modulation of early vascular events. J Neurosci 22:7526–7535

    PubMed  CAS  Google Scholar 

  • Reeves TM, Prins ML, Zhu J, Povlishock JT, Phillips LL (2003) Matrix metalloproteinase inhibition alters functional and structural correlates of deafferentation-induced sprouting in the dentate gyrus. J Neurosci 23:10182–10189

    PubMed  CAS  Google Scholar 

  • Rosenberg GA (1995) Matrix metalloproteinases in brain injury. J Neurotrauma 12:833–842

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg GA, Estrada EY, Dencoff JE, Stetler-Stevenson WG (1995) Tumor necrosis factor-alpha-induced gelatinase B causes delayed opening of the blood-brain barrier: an expanded therapeutic window. Brain Res 703:151–155

    Article  PubMed  CAS  Google Scholar 

  • Rosenberg GA, Estrada EY, Dencoff JE (1998) Matrix metalloproteinases and TIMPs are associated with blood–brain barrier opening after reperfusion in rat brain. Stroke 29:2189–2195

    Article  PubMed  CAS  Google Scholar 

  • Skelton L, Cooper M, Murphy M, Platt A (2003) Human immature monocyte-derived dendritic cells express the G protein-coupled receptor GPR105 (KIAA0001, P2Y14) and increase intracellular calcium in response to its agonist, uridine diphosphoglucose. J Immunol 171:1941–1949

    PubMed  CAS  Google Scholar 

  • Slezak M, Pfrieger FW (2003) New roles for astrocytes: regulation of CNS synaptogenesis. Trends Neurosci 26:531–535

    Article  PubMed  CAS  Google Scholar 

  • Takata F, Dohgu S, Matsumoto J, Takahashi H, Machida T, Wakigawa T, Harada E, Miyaji H, Koga M, Nishioku T, Yamauchi A, Kataoka Y (2011) Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-alpha, releasing matrix metalloproteinase-9 and migrating in vitro. J Neuroinflamm 8:106

    Article  CAS  Google Scholar 

  • Tsai HH, Li H, Fuentealba LC, Molofsky AV, Taveira-Marques R, Zhuang H, Tenney A, Murnen AT, Fancy SP, Merkle F, Kessaris Ns, Alvarez-Buylla A, Richardson WD, Rowitch DH (2012) Regional astrocyte allocation regulates CNS synaptogenesis and repair. Science 337:358–362

    Article  PubMed  CAS  Google Scholar 

  • Wu CY, Hsieh HL, Jou MJ, Yang CM (2004) Involvement of p42/p44 MAPK, p38 MAPK, JNK and nuclear factor-kappa B in interleukin-1beta-induced matrix metalloproteinase-9 expression in rat brain astrocytes. J Neurochem 90:1477–1488

    Article  PubMed  CAS  Google Scholar 

  • Yan P, Hu X, Song H, Yin K, Bateman RJ, Cirrito JR, Xiao Q, Hsu FF, Turk JW, Xu J, Hsu CY, Holtzman DM, Lee JM (2006) Matrix metalloproteinase-9 degrades amyloid-beta fibrils in vitro and compact plaques in situ. J Biol Chem 281:24566–24574

    Article  PubMed  CAS  Google Scholar 

  • Yang Y, Estrada EY, Thompson JF, Liu W, Rosenberg GA (2006) Matrix metalloproteinase-mediated disruption of tight junction proteins in cerebral vessels is reversed by synthetic matrix metalloproteinase inhibitor in focal ischemia in rat. J Cereb Blood Flow Metab 27(4):697–709

    PubMed  Google Scholar 

  • Zhao BQ, Wang S, Kim HY, Storrie H, Rosen BR, Mooney DJ, Wang X, Lo EH (2006) Role of matrix metalloproteinases in delayed cortical responses after stroke. Nat Med 12:441–445

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

We thank Koizumi’s lab members for helpful comments and/or discussion. We also thank Dr. T. Kawanishi for kindly supplying us some reagents. ARC-69931 was from AstraZeneca. This study was partly supported by CREST, a grant from Takeda Science foundation, Sumitomo Foundation, a Grant-in-Aid for Scientific Research (A) and on Priority Areas from the Ministry of Education, Science, Sports and Culture of Japan, a Grant-in-Aid from Food Safety Commission Japan.

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Authors and Affiliations

  1. Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, 1110 Shimokato, Chuo, Yamanashi, 409-3898, Japan

    Manao Kinoshita, Kayoko Fujishita & Schuichi Koizumi

  2. Division of Pharmacology, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya, Tokyo, 158-8501, Japan

    Kaoru Nasu-Tada & Kaoru Sato

  3. Japan Science and Technology Agency, Core Research for Evolutional Science and Technology, Tokyo, 102-0076, Japan

    Schuichi Koizumi

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  1. Manao Kinoshita
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  2. Kaoru Nasu-Tada
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  3. Kayoko Fujishita
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  4. Kaoru Sato
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  5. Schuichi Koizumi
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Correspondence to Schuichi Koizumi.

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Manao Kinoshita, Kaoru Nasu-Tada and Kayoko Fujishita contributed equally to this work.

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Kinoshita, M., Nasu-Tada, K., Fujishita, K. et al. Secretion of Matrix Metalloproteinase-9 from Astrocytes by Inhibition of Tonic P2Y14-Receptor-Mediated Signal(s). Cell Mol Neurobiol 33, 47–58 (2013). https://doi.org/10.1007/s10571-012-9869-4

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