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Journal of Neuroinflammation
Published in: Journal of Neuroinflammation 1/2011

Open Access 01-12-2011 | Research

Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-α, releasing matrix metalloproteinase-9 and migrating in vitro

Authors: Fuyuko Takata, Shinya Dohgu, Junichi Matsumoto, Hiroyuki Takahashi, Takashi Machida, Tomoya Wakigawa, Eriko Harada, Haruki Miyaji, Mitsuhisa Koga, Tsuyoshi Nishioku, Atsushi Yamauchi, Yasufumi Kataoka

Published in: Journal of Neuroinflammation | Issue 1/2011

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Abstract

Background

Increased matrix metalloproteinase (MMP)-9 in the plasma and brain is associated with blood-brain barrier (BBB) disruption through proteolytic activity in neuroinflammatory diseases. MMP-9 is present in the brain microvasculature and its vicinity, where brain microvascular endothelial cells (BMECs), pericytes and astrocytes constitute the BBB. Little is known about the cellular source and role of MMP-9 at the BBB. Here, we examined the ability of pericytes to release MMP-9 and migrate in response to inflammatory mediators in comparison with BMECs and astrocytes, using primary cultures isolated from rat brains.

Methods

The culture supernatants were collected from primary cultures of rat brain endothelial cells, pericytes, or astrocytes. MMP-9 activities and levels in the supernatants were measured by gelatin zymography and western blot, respectively. The involvement of signaling molecules including mitogen-activated protein kinases (MAPKs) and phosphoinositide-3-kinase (PI3K)/Akt in the mediation of tumor necrosis factor (TNF)-α-induced MMP-9 release was examined using specific inhibitors. The functional activity of MMP-9 was evaluated by a cell migration assay.

Results

Zymographic and western blot analyses demonstrated that TNF-α stimulated pericytes to release MMP-9, and this release was much higher than from BMECs or astrocytes. Other inflammatory mediators [interleukin (IL)-1β, interferon-γ, IL-6 and lipopolysaccharide] failed to induce MMP-9 release from pericytes. TNF-α-induced MMP-9 release from pericytes was found to be mediated by MAPKs and PI3K. Scratch wound healing assay showed that in contrast to BMECs and astrocytes the extent of pericyte migration was significantly increased by TNF-α. This pericyte migration was inhibited by anti-MMP-9 antibody.

Conclusion

These findings suggest that pericytes are most sensitive to TNF-α in terms of MMP-9 release, and are the major source of MMP-9 at the BBB. This pericyte-derived MMP-9 initiated cellular migration of pericytes, which might be involved in pericyte loss in the damaged BBB.
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Literature
1.
Takata F, Dohgu S, Nishioku T, Takahashi H, Harada E, Makino I, Nakashima M, Yamauchi A, Kataoka Y: Adrenomedullin-induced relaxation of rat brain pericytes is related to the reduced phosphorylation of myosin light chain through the cAMP/PKA signaling pathway. Neurosci Lett. 2009, 449: 71-75. 10.1016/j.neulet.2008.10.082.CrossRefPubMed
2.
Peppiatt CM, Howarth C, Mobbs P, Attwell D: Bidirectional control of CNS capillary diameter by pericytes. Nature. 2006, 443: 700-704. 10.1038/nature05193.PubMedCentralCrossRefPubMed
3.
Yemisci M, Gursoy-Ozdemir Y, Vural A, Can A, Topalkara K, Dalkara T: Pericyte contraction induced by oxidative-nitrative stress impairs capillary reflow despite successful opening of an occluded cerebral artery. Nat Med. 2009, 15: 1031-1037. 10.1038/nm.2022.CrossRefPubMed
4.
Dohgu S, Takata F, Yamauchi A, Nakagawa S, Egawa T, Naito M, Tsuruo T, Sawada Y, Niwa M, Kataoka Y: Brain pericytes contribute to the induction and up-regulation of blood-brain barrier functions through transforming growth factor-beta production. Brain Res. 2005, 1038: 208-215. 10.1016/j.brainres.2005.01.027.CrossRefPubMed
5.
Hori S, Ohtsuki S, Hosoya K, Nakashima E, Terasaki T: A pericyte-derived angiopoietin-1 multimeric complex induces occludin gene expression in brain capillary endothelial cells through Tie-2 activation in vitro. J Neurochem. 2004, 89: 503-513. 10.1111/j.1471-4159.2004.02343.x.CrossRefPubMed
6.
Dohgu S, Takata F, Matsumoto J, Oda M, Harada E, Watanabe T, Nishioku T, Shuto H, Yamauchi A, Kataoka Y: Autocrine and paracrine up-regulation of blood-brain barrier function by plasminogen activator inhibitor-1. Microvasc Res. 2011, 81: 103-107. 10.1016/j.mvr.2010.10.004.CrossRefPubMed
7.
Nakagawa S, Deli MA, Kawaguchi H, Shimizudani T, Shimono T, Kittel A, Tanaka K, Niwa M: A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int. 2009, 54: 253-263. 10.1016/j.neuint.2008.12.002.CrossRefPubMed
8.
Takata F, Dohgu S, Yamauchi A, Sumi N, Nakagawa S, Naito M, Tsuruo T, Shuto H, Kataoka Y: Inhibition of transforming growth factor-beta production in brain pericytes contributes to cyclosporin A-induced dysfunction of the blood-brain barrier. Cell Mol Neurobiol. 2007, 27: 317-328. 10.1007/s10571-006-9125-x.CrossRefPubMed
9.
Bell RD, Winkler EA, Sagare AP, Singh I, LaRue B, Deane R, Zlokovic BV: Pericytes control key neurovascular functions and neuronal phenotype in the adult brain and during brain aging. Neuron. 2010, 68: 409-427. 10.1016/j.neuron.2010.09.043.PubMedCentralCrossRefPubMed
10.
Armulik A, Genove G, Mae M, Nisancioglu MH, Wallgard E, Niaudet C, He L, Norlin J, Lindblom P, Strittmatter K, et al: Pericytes regulate the blood-brain barrier. Nature. 2010, 468: 557-561. 10.1038/nature09522.CrossRefPubMed
11.
Nishioku T, Dohgu S, Takata F, Eto T, Ishikawa N, Kodama KB, Nakagawa S, Yamauchi A, Kataoka Y: Detachment of brain pericytes from the basal lamina is involved in disruption of the blood-brain barrier caused by lipopolysaccharide-induced sepsis in mice. Cell Mol Neurobiol. 2009, 29: 309-316. 10.1007/s10571-008-9322-x.CrossRefPubMed
12.
Weiss N, Miller F, Cazaubon S, Couraud PO: The blood-brain barrier in brain homeostasis and neurological diseases. Biochim Biophys Acta. 2009, 1788: 842-857. 10.1016/j.bbamem.2008.10.022.CrossRefPubMed
13.
Melgar MA, Rafols J, Gloss D, Diaz FG: Postischemic reperfusion: ultrastructural blood-brain barrier and hemodynamic correlative changes in an awake model of transient forebrain ischemia. Neurosurgery. 2005, 56: 571-581. 10.1227/01.NEU.0000154702.23664.3D.CrossRefPubMed
14.
Gonul E, Duz B, Kahraman S, Kayali H, Kubar A, Timurkaynak E: Early pericyte response to brain hypoxia in cats: an ultrastructural study. Microvasc Res. 2002, 64: 116-119. 10.1006/mvre.2002.2413.CrossRefPubMed
15.
Dore-Duffy P, Owen C, Balabanov R, Murphy S, Beaumont T, Rafols JA: Pericyte migration from the vascular wall in response to traumatic brain injury. Microvasc Res. 2000, 60: 55-69. 10.1006/mvre.2000.2244.CrossRefPubMed
16.
Krueger M, Bechmann I: CNS pericytes: concepts, misconceptions, and a way out. Glia. 2010, 58: 1-10. 10.1002/glia.20898.CrossRefPubMed
17.
Romanic AM, White RF, Arleth AJ, Ohlstein EH, Barone FC: Matrix metalloproteinase expression increases after cerebral focal ischemia in rats: inhibition of matrix metalloproteinase-9 reduces infarct size. Stroke. 1998, 29: 1020-1030. 10.1161/01.STR.29.5.1020.CrossRefPubMed
18.
Lee SR, Tsuji K, Lo EH: Role of matrix metalloproteinases in delayed neuronal damage after transient global cerebral ischemia. J Neurosci. 2004, 24: 671-678. 10.1523/JNEUROSCI.4243-03.2004.CrossRefPubMed
19.
Bauer AT, Burgers HF, Rabie T, Marti HH: Matrix metalloproteinase-9 mediates hypoxia-induced vascular leakage in the brain via tight junction rearrangement. J Cereb Blood Flow Metab. 2010, 30: 837-848. 10.1038/jcbfm.2009.248.PubMedCentralCrossRefPubMed
20.
Gasche Y, Copin JC, Sugawara T, Fujimura M, Chan PH: Matrix metalloproteinase inhibition prevents oxidative stress-associated blood-brain barrier disruption after transient focal cerebral ischemia. J Cereb Blood Flow Metab. 2001, 21: 1393-1400.CrossRefPubMed
21.
McColl BW, Rose N, Robson FH, Rothwell NJ, Lawrence CB: Increased brain microvascular MMP-9 and incidence of haemorrhagic transformation in obese mice after experimental stroke. J Cereb Blood Flow Metab. 2010, 30: 267-272. 10.1038/jcbfm.2009.217.PubMedCentralCrossRefPubMed
22.
Nakagawa S, Deli MA, Nakao S, Honda M, Hayashi K, Nakaoke R, Kataoka Y, Niwa M: Pericytes from brain microvessels strengthen the barrier integrity in primary cultures of rat brain endothelial cells. Cell Mol Neurobiol. 2007, 27: 687-694. 10.1007/s10571-007-9195-4.CrossRefPubMed
23.
Takata F, Sumi N, Nishioku T, Harada E, Wakigawa T, Shuto H, Yamauchi A, Kataoka Y: Oncostatin M induces functional and structural impairment of blood-brain barriers comprised of rat brain capillary endothelial cells. Neurosci Lett. 2008, 441: 163-166. 10.1016/j.neulet.2008.06.030.CrossRefPubMed
24.
McCarthy KD, de Vellis J: Preparation of separate astroglial and oligodendroglial cell cultures from rat cerebral tissue. J Cell Biol. 1980, 85: 890-902. 10.1083/jcb.85.3.890.CrossRefPubMed
25.
Rosenberg GA: Matrix metalloproteinases and their multiple roles in neurodegenerative diseases. Lancet Neurol. 2009, 8: 205-216. 10.1016/S1474-4422(09)70016-X.CrossRefPubMed
26.
Kolev K, Skopal J, Simon L, Csonka E, Machovich R, Nagy Z: Matrix metalloproteinase-9 expression in post-hypoxic human brain capillary endothelial cells: H2O2 as a trigger and NF-kappaB as a signal transducer. Thromb Haemost. 2003, 90: 528-537.PubMed
27.
Hsieh HL, Wu CY, Yang CM: Bradykinin induces matrix metalloproteinase-9 expression and cell migration through a PKC-delta-dependent ERK/Elk-1 pathway in astrocytes. Glia. 2008, 56: 619-632. 10.1002/glia.20637.CrossRefPubMed
28.
Thanabalasundaram G, Pieper C, Lischper M, Galla HJ: Regulation of the blood-brain barrier integrity by pericytes via matrix metalloproteinases mediated activation of vascular endothelial growth factor in vitro. Brain Res. 2010, 1347: 1-10.CrossRefPubMed
29.
Wu CY, Hsieh HL, Sun CC, Yang CM: IL-1 beta induces MMP-9 expression via a Ca2+-dependent CaMKII/JNK/c-JUN cascade in rat brain astrocytes. Glia. 2009, 57: 1775-1789. 10.1002/glia.20890.CrossRefPubMed
30.
Crocker SJ, Frausto RF, Whitton JL, Milner R: A novel method to establish microglia-free astrocyte cultures: comparison of matrix metalloproteinase expression profiles in pure cultures of astrocytes and microglia. Glia. 2008, 56: 1187-1198. 10.1002/glia.20689.PubMedCentralCrossRefPubMed
31.
Adya R, Tan BK, Punn A, Chen J, Randeva HS: Visfatin induces human endothelial VEGF and MMP-2/9 production via MAPK and PI3K/Akt signalling pathways: novel insights into visfatin-induced angiogenesis. Cardiovasc Res. 2008, 78: 356-365. 10.1093/cvr/cvm111.CrossRefPubMed
32.
Cheng G, Wei L, Xiurong W, Xiangzhen L, Shiguang Z, Songbin F: IL-17 stimulates migration of carotid artery vascular smooth muscle cells in an MMP-9 dependent manner via p38 MAPK and ERK1/2-dependent NF-kappaB and AP-1 activation. Cell Mol Neurobiol. 2009, 29: 1161-1168. 10.1007/s10571-009-9409-z.CrossRefPubMed
33.
Choi MS, Cho KS, Shin SM, Ko HM, Kwon KJ, Shin CY, Ko KH: ATP induced microglial cell migration through non-transcriptional activation of matrix metalloproteinase-9. Arch Pharm Res. 2010, 33: 257-265. 10.1007/s12272-010-0211-8.CrossRefPubMed
34.
Plaisance I, Morandi C, Murigande C, Brink M: TNF-alpha increases protein content in C2C12 and primary myotubes by enhancing protein translation via the TNF-R1, PI3K, and MEK. Am J Physiol Endocrinol Metab. 2008, 294: E241-250.CrossRefPubMed
35.
Faustman D, Davis M: TNF receptor 2 pathway: drug target for autoimmune diseases. Nat Rev Drug Discov. 2010, 9: 482-493. 10.1038/nrd3030.CrossRefPubMed
36.
Mantuano E, Inoue G, Li X, Takahashi K, Gaultier A, Gonias SL, Campana WM: The hemopexin domain of matrix metalloproteinase-9 activates cell signaling and promotes migration of schwann cells by binding to low-density lipoprotein receptor-related protein. J Neurosci. 2008, 28: 11571-11582. 10.1523/JNEUROSCI.3053-08.2008.CrossRefPubMed
37.
Kang SS, Kook JH, Hwang S, Park SH, Nam SC, Kim JK: Inhibition of matrix metalloproteinase-9 attenuated neural progenitor cell migration after photothrombotic ischemia. Brain Res. 2008, 1228: 20-26.CrossRefPubMed
38.
Heissig B, Rafii S, Akiyama H, Ohki Y, Sato Y, Rafael T, Zhu Z, Hicklin DJ, Okumura K, Ogawa H, et al: Low-dose irradiation promotes tissue revascularization through VEGF release from mast cells and MMP-9-mediated progenitor cell mobilization. J Exp Med. 2005, 202: 739-750. 10.1084/jem.20050959.PubMedCentralCrossRefPubMed
39.
Radjabi AR, Sawada K, Jagadeeswaran S, Eichbichler A, Kenny HA, Montag A, Bruno K, Lengyel E: Thrombin induces tumor invasion through the induction and association of matrix metalloproteinase-9 and beta1-integrin on the cell surface. J Biol Chem. 2008, 283: 2822-2834.PubMedCentralCrossRefPubMed
40.
Petty MA, Lo EH: Junctional complexes of the blood-brain barrier: permeability changes in neuroinflammation. Prog Neurobiol. 2002, 68: 311-323. 10.1016/S0301-0082(02)00128-4.CrossRefPubMed
41.
Lorenzl S, Albers DS, Narr S, Chirichigno J, Beal MF: Expression of MMP-2, MMP-9, and MMP-1 and their endogenous counterregulators TIMP-1 and TIMP-2 in postmortem brain tissue of Parkinson's disease. Exp Neurol. 2002, 178: 13-20. 10.1006/exnr.2002.8019.CrossRefPubMed
42.
Yang GY, Gong C, Qin Z, Liu XH, Lorris Betz A: Tumor necrosis factor alpha expression produces increased blood-brain barrier permeability following temporary focal cerebral ischemia in mice. Brain Res Mol Brain Res. 1999, 69: 135-143.CrossRefPubMed
43.
Fujimura M, Gasche Y, Morita-Fujimura Y, Massengale J, Kawase M, Chan PH: Early appearance of activated matrix metalloproteinase-9 and blood-brain barrier disruption in mice after focal cerebral ischemia and reperfusion. Brain Res. 1999, 842: 92-100. 10.1016/S0006-8993(99)01843-0.CrossRefPubMed
44.
Leib SL, Leppert D, Clements J, Tauber MG: Matrix metalloproteinases contribute to brain damage in experimental pneumococcal meningitis. Infect Immun. 2000, 68: 615-620. 10.1128/IAI.68.2.615-620.2000.PubMedCentralCrossRefPubMed
45.
Tsuge M, Yasui K, Ichiyawa T, Saito Y, Nagaoka Y, Yashiro M, Yamashita N, Morishima T: Increase of tumor necrosis factor-alpha in the blood induces early activation of matrix metalloproteinase-9 in the brain. Microbiol Immunol. 2010, 54: 417-424.PubMed
46.
47.
Verma S, Nakaoke R, Dohgu S, Banks WA: Release of cytokines by brain endothelial cells: A polarized response to lipopolysaccharide. Brain Behav Immun. 2006, 20: 449-455. 10.1016/j.bbi.2005.10.005.CrossRefPubMed
48.
Nishioku T, Matsumoto J, Dohgu S, Sumi N, Miyao K, Takata F, Shuto H, Yamauchi A, Kataoka Y: Tumor necrosis factor-alpha mediates the blood-brain barrier dysfunction induced by activated microglia in mouse brain microvascular endothelial cells. J Pharmacol Sci. 2010, 112: 251-254. 10.1254/jphs.09292SC.CrossRefPubMed
49.
Viviani B, Corsini E, Galli CL, Marinovich M: Glia increase degeneration of hippocampal neurons through release of tumor necrosis factor-alpha. Toxicol Appl Pharmacol. 1998, 150: 271-276. 10.1006/taap.1998.8406.CrossRefPubMed
Metadata
Title
Brain pericytes among cells constituting the blood-brain barrier are highly sensitive to tumor necrosis factor-α, releasing matrix metalloproteinase-9 and migrating in vitro
Authors
Fuyuko Takata
Shinya Dohgu
Junichi Matsumoto
Hiroyuki Takahashi
Takashi Machida
Tomoya Wakigawa
Eriko Harada
Haruki Miyaji
Mitsuhisa Koga
Tsuyoshi Nishioku
Atsushi Yamauchi
Yasufumi Kataoka
Publication date
01-12-2011
Publisher
BioMed Central
Published in
Journal of Neuroinflammation / Issue 1/2011
Electronic ISSN: 1742-2094
DOI
https://doi.org/10.1186/1742-2094-8-106

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