Increased matrix metalloproteinases expression in tuberous sclerosis complex: modulation by microRNA 146a and 147b in vitro.
blood-brain barrier
extracellular matrix
matrix metalloproteinases
microRNA
tuberous sclerosis complex
Journal
Neuropathology and applied neurobiology
ISSN: 1365-2990
Titre abrégé: Neuropathol Appl Neurobiol
Pays: England
ID NLM: 7609829
Informations de publication
Date de publication:
02 2020
02 2020
Historique:
received:
14
01
2019
accepted:
05
06
2019
pubmed:
12
6
2019
medline:
5
2
2021
entrez:
12
6
2019
Statut:
ppublish
Résumé
Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) control proteolysis within the extracellular matrix (ECM) of the brain. Dysfunction of this enzymatic system due to brain inflammation can disrupt the blood-brain barrier (BBB) and has been implicated in the pathogenesis of epilepsy. However, this has not been extensively studied in the epileptogenic human brain. We investigated the expression and cellular localization of major MMPs (MMP2, MMP3, MMP9 and MMP14) and TIMPs (TIMP1, TIMP2, TIMP3 and TIMP4) using quantitative real-time polymerase chain reaction (RT-PCR) and immunohistochemistry in resected epileptogenic brain tissue from patients with tuberous sclerosis complex (TSC), a severe neurodevelopmental disorder characterized by intractable epilepsy and prominent neuroinflammation. Furthermore, we determined whether anti-inflammatory microRNAs, miR146a and miR147b, which can regulate gene expression at the transcriptional level, could attenuate dysregulated MMP and TIMP expression in TSC tuber-derived astroglial cultures. We demonstrated higher mRNA and protein expression of MMPs and TIMPs in TSC tubers compared to control and perituberal brain tissue, particularly in dysmorphic neurons and giant cells, as well as in reactive astrocytes, which was associated with BBB dysfunction. More importantly, IL-1β-induced dysregulation of MMP3, TIMP2, TIMP3 and TIMP4 could be rescued by miR146a and miR147b in tuber-derived TSC cultures. This study provides evidence of dysregulation of the MMP/TIMP proteolytic system in TSC, which is associated with BBB dysfunction. As dysregulated MMP and TIMP expression can be ameliorated in vitro by miR146a and miR147b, these miRNAs deserve further investigation as a novel therapeutic approach.
Identifiants
pubmed: 31183875
doi: 10.1111/nan.12572
pmc: PMC7217197
doi:
Substances chimiques
MIRN146 microRNA, human
0
MIRN147 microRNA, human
0
MicroRNAs
0
Tissue Inhibitor of Metalloproteinases
0
Matrix Metalloproteinases
EC 3.4.24.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
142-159Informations de copyright
© 2019 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society.
Références
Glia. 2018 May;66(5):1082-1097
pubmed: 29384235
Matrix Biol. 2015 May-Jul;44-46:247-54
pubmed: 25805621
J Neuroinflammation. 2013 Jan 24;10:12
pubmed: 23347564
Cell. 2007 Jun 29;129(7):1261-74
pubmed: 17604717
J Cell Physiol. 2006 Jan;206(1):68-77
pubmed: 15920760
Epilepsia. 2017 Aug;58(8):1462-1472
pubmed: 28643873
Am J Physiol Heart Circ Physiol. 2005 Aug;289(2):H558-68
pubmed: 15764676
EMBO J. 2001 Sep 3;20(17):4782-93
pubmed: 11532942
Glia. 2016 Jun;64(6):1066-82
pubmed: 27014996
J Neurosci. 2010 Nov 17;30(46):15337-57
pubmed: 21084591
Biochemistry. 2002 Jul 30;41(30):9462-9
pubmed: 12135369
Acta Neuropathol. 2013 Mar;125(3):317-32
pubmed: 23386324
J Neurochem. 2012 Oct;123(2):203-16
pubmed: 22862420
PLoS One. 2012;7(9):e44789
pubmed: 23028621
Lancet. 2008 Aug 23;372(9639):657-68
pubmed: 18722871
Cell Signal. 2007 Aug;19(8):1643-51
pubmed: 17376651
Brain. 2016 Oct;139(Pt 10):2653-2667
pubmed: 27497492
Curr Vasc Pharmacol. 2015;13(2):161-6
pubmed: 24188490
Semin Cell Dev Biol. 2015 Feb;38:26-34
pubmed: 25444846
Science. 1997 Jul 11;277(5323):225-8
pubmed: 9211848
Eur J Neurosci. 2003 May;17(10):2106-18
pubmed: 12786977
Mol Neurobiol. 2014 Feb;49(1):563-73
pubmed: 24026771
Brain Pathol. 2010 Jul;20(4):704-19
pubmed: 19912235
PLoS One. 2011;6(8):e20599
pubmed: 21857898
J Cereb Blood Flow Metab. 2016 Sep;36(9):1481-507
pubmed: 27323783
Brain Res. 2012 May 9;1453:46-55
pubmed: 22459050
Mol Cell Neurosci. 2003 Oct;24(2):395-408
pubmed: 14572461
J Immunol. 1998 Oct 1;161(7):3340-6
pubmed: 9759850
Neurobiol Dis. 2017 Mar;99:12-23
pubmed: 27939857
Dis Model Mech. 2015 Sep;8(9):1081-91
pubmed: 26112171
J Neurosurg. 2011 Jan;114(1):92-101
pubmed: 20617879
Neuropathol Appl Neurobiol. 2020 Feb;46(2):142-159
pubmed: 31183875
Epilepsia. 2012 Nov;53(11):1877-86
pubmed: 22905812
Biochim Biophys Acta. 2000 Mar 7;1477(1-2):267-83
pubmed: 10708863
Oncogene. 2008 Sep 18;27(42):5643-7
pubmed: 18504431
Neuroscience. 2010 Mar 17;166(2):508-21
pubmed: 20045450
Epilepsia. 2018 Oct;59(10):1931-1944
pubmed: 30194729
Am J Physiol Heart Circ Physiol. 2018 Apr 1;314(4):H693-H703
pubmed: 29351469
J Neurochem. 2012 Jan;120(1):147-56
pubmed: 22007835
Trends Immunol. 2001 Oct;22(10):571-9
pubmed: 11574282
Epilepsia. 2011 Oct;52 Suppl 8:19-20
pubmed: 21967353
Brain Pathol. 2013 Jan;23(1):45-59
pubmed: 22805177
Neurobiol Dis. 2009 May;34(2):189-98
pubmed: 19200854
Neurosurg Focus. 2007 May 15;22(5):E4
pubmed: 17613235
PLoS One. 2015 Sep 02;10(9):e0136797
pubmed: 26331622
J Biol Chem. 1995 Dec 22;270(51):30479-85
pubmed: 8530478
Am J Physiol. 1998 May;274(5):R1203-11
pubmed: 9644031
Eur J Paediatr Neurol. 2016 Mar;20(2):203-211
pubmed: 26758984
J Neuroimmunol. 2005 Mar;160(1-2):188-94
pubmed: 15710472
Turk Neurosurg. 2015;25(5):749-56
pubmed: 26442541
Epilepsy Res. 2013 Mar;104(1-2):45-58
pubmed: 23182966
Sci Rep. 2017 Sep 14;7(1):11592
pubmed: 28912503
J Neuroinflammation. 2016 Aug 26;13(1):202
pubmed: 27566410
Cell Mol Life Sci. 2012 Sep;69(18):3127-45
pubmed: 22535415
Exp Neurol. 2006 Jul;200(1):38-49
pubmed: 16624294
Circ Res. 2003 May 2;92(8):827-39
pubmed: 12730128
Stem Cells. 2008 Dec;26(12):3139-49
pubmed: 18818437
Crit Rev Biochem Mol Biol. 2010 Oct;45(5):351-423
pubmed: 20812779
Thromb Haemost. 2001 Jul;86(1):324-33
pubmed: 11487021
Sci Rep. 2017 Aug 14;7(1):8089
pubmed: 28808237
Immune Netw. 2011 Jun;11(3):135-54
pubmed: 21860607
Prostate. 2012 Aug 1;72(11):1171-8
pubmed: 22161865
Blood. 2000 Oct 15;96(8):2673-81
pubmed: 11023497
J Cereb Blood Flow Metab. 2003 Dec;23(12):1430-40
pubmed: 14663338
J Biol Chem. 2007 Jun 1;282(22):16036-41
pubmed: 17426029
Brain. 2007 Feb;130(Pt 2):521-34
pubmed: 17124188
PLoS One. 2008 Jul 16;3(7):e2681
pubmed: 18629001
J Cereb Blood Flow Metab. 2007 Apr;27(4):697-709
pubmed: 16850029
Expert Rev Neurother. 2008 Mar;8(3):457-67
pubmed: 18345974
Epilepsy Res. 2008 Jan;78(1):7-21
pubmed: 18023148
N Engl J Med. 2006 Sep 28;355(13):1345-56
pubmed: 17005952
Biochim Biophys Acta. 2010 Jan;1803(1):55-71
pubmed: 20080133
Brain Res. 1992 Apr 3;576(2):203-7
pubmed: 1381261
J Neuroinflammation. 2018 Jul 21;15(1):211
pubmed: 30031401
PLoS One. 2015 Jul 30;10(7):e0134352
pubmed: 26226628
Neurobiol Dis. 2014 Feb;62:508-20
pubmed: 24184920
Eur J Neurosci. 2010 Mar;31(6):1100-7
pubmed: 20214679
Glia. 2005 Jun;50(4):329-39
pubmed: 15846802
Nucleic Acids Res. 2009 Apr;37(6):e45
pubmed: 19237396
Hepatol Res. 2009 Feb;39(2):177-86
pubmed: 19208038
Brain Res. 2013 Nov 13;1538:172-81
pubmed: 24095794
Expert Rev Neurother. 2018 Mar;18(3):185-201
pubmed: 29338461
J Neurosci. 2004 Sep 8;24(36):7829-36
pubmed: 15356194