Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275.
Acute Disease
Adrenoleukodystrophy
/ drug therapy
Adult
Autopsy
Benzamides
/ pharmacology
Foam Cells
/ drug effects
Gene Expression Profiling
Histone Deacetylase Inhibitors
/ pharmacology
Humans
Immunohistochemistry
Inflammation
/ drug therapy
Middle Aged
Multiple Sclerosis
/ drug therapy
Pyridines
/ pharmacology
Sequence Analysis, RNA
Young Adult
Journal
Annals of clinical and translational neurology
ISSN: 2328-9503
Titre abrégé: Ann Clin Transl Neurol
Pays: United States
ID NLM: 101623278
Informations de publication
Date de publication:
11 2020
11 2020
Historique:
received:
08
07
2020
revised:
25
08
2020
accepted:
30
08
2020
pubmed:
1
10
2020
medline:
25
9
2021
entrez:
30
9
2020
Statut:
ppublish
Résumé
To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD). Immunohistochemistry on postmortem brain tissue of acute MS (n = 6) and cerebral ALD (n = 4) cases to analyze activation and foam cell state of phagocytes. RNA-Seq of in vitro differentiated healthy macrophages (n = 8) after sustained myelin-loading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages. Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRα/PPARγ pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells. These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.
Identifiants
pubmed: 32997393
doi: 10.1002/acn3.51200
pmc: PMC7664285
doi:
Substances chimiques
Benzamides
0
Histone Deacetylase Inhibitors
0
Pyridines
0
entinostat
1ZNY4FKK9H
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2161-2177Subventions
Organisme : Austrian Science Fund FWF
ID : DOC 33
Pays : Austria
Organisme : Austrian Science Fund FWF
ID : P 28705
Pays : Austria
Informations de copyright
© 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
Références
PLoS One. 2014 Sep 25;9(9):e108655
pubmed: 25255441
J Neurol Sci. 1992 Jul;110(1-2):195-204
pubmed: 1506859
Mutat Res. 2010 Aug 7;690(1-2):57-63
pubmed: 20973164
PLoS One. 2012;7(9):e44998
pubmed: 22984598
Mol Cell Biol. 1999 Aug;19(8):5504-11
pubmed: 10409740
Exp Neurol. 2013 Mar;241:56-66
pubmed: 23261766
Redox Biol. 2019 Jun;24:101198
pubmed: 31048245
Int Rev Immunol. 2015 Jan;34(1):82-100
pubmed: 25340307
Biochimie. 2014 Mar;98:135-42
pubmed: 24316281
Acta Neuropathol Commun. 2013 Aug 02;1:43
pubmed: 24252308
J Neurosci. 2006 Jan 4;26(1):328-32
pubmed: 16399703
Nat Med. 1998 Nov;4(11):1261-8
pubmed: 9809549
Biochim Biophys Acta. 2012 Sep;1822(9):1465-74
pubmed: 22483867
Acta Neuropathol Commun. 2018 Nov 19;6(1):124
pubmed: 30454040
Brain Pathol. 2018 Nov;28(6):902-919
pubmed: 29476661
Mol Genet Metab. 2017 Dec;122(4):209-215
pubmed: 29089175
Nature. 2011 Aug 24;477(7364):340-3
pubmed: 21866103
Ann Clin Transl Neurol. 2015 Oct 27;2(12):1071-84
pubmed: 26734659
J Biol Chem. 2013 Jun 28;288(26):19269-79
pubmed: 23671276
Nature. 2005 Sep 29;437(7059):759-63
pubmed: 16127449
Hum Mol Genet. 2004 Dec 1;13(23):2997-3006
pubmed: 15489218
Cell Metab. 2005 Feb;1(2):121-31
pubmed: 16054053
Nat Rev Endocrinol. 2016 Oct;12(10):606-15
pubmed: 27312864
Trends Immunol. 2004 Dec;25(12):677-86
pubmed: 15530839
EMBO Mol Med. 2014 Jul 09;6(9):1124-32
pubmed: 25007801
Trends Immunol. 2019 Dec;40(12):1163-1179
pubmed: 31732284
J Biol Chem. 2005 Dec 16;280(50):41243-51
pubmed: 16249184
Science. 2018 Feb 9;359(6376):684-688
pubmed: 29301957
Science. 2009 Nov 6;326(5954):818-23
pubmed: 19892975
Ann Clin Transl Neurol. 2020 May;7(5):639-652
pubmed: 32359032
J Clin Invest. 2007 Aug;117(8):2216-24
pubmed: 17657311
Brain. 2009 May;132(Pt 5):1175-89
pubmed: 19339255
Arch Neurol. 1975 Sep;32(9):577-91
pubmed: 169765
PLoS One. 2018 Mar 26;13(3):e0194661
pubmed: 29579087
Hum Mol Genet. 2002 Oct 15;11(22):2701-8
pubmed: 12374760
Hum Mol Genet. 1999 May;8(5):907-13
pubmed: 10196381
Neuron. 2014 Sep 3;83(5):1098-116
pubmed: 25132469
Brain. 2006 Feb;129(Pt 2):517-26
pubmed: 16364958
J Neurochem. 1976 Apr;26(4):851-60
pubmed: 965973
Biochim Biophys Acta. 2006 Dec;1763(12):1721-32
pubmed: 16949688
Biochem Biophys Res Commun. 2014 Dec 12;455(3-4):396-402
pubmed: 25446073
J Neuroinflammation. 2011 Mar 15;8:24
pubmed: 21401967
Biol Blood Marrow Transplant. 2019 Mar;25(3):538-548
pubmed: 30292747
Nature. 2013 Apr 25;496(7446):445-55
pubmed: 23619691
Curr Opin Lipidol. 2014 Oct;25(5):367-73
pubmed: 25188918
Nat Neurosci. 2011 Jan;14(1):45-53
pubmed: 21131950
Brain. 2018 Aug 1;141(8):2329-2342
pubmed: 29860501
Mol Cell. 2009 May 14;34(4):510-8
pubmed: 19481530
Mult Scler. 2018 Mar;24(3):279-289
pubmed: 28273782
Hum Mol Genet. 2014 May 15;23(10):2542-50
pubmed: 24363066
Nat Rev Neurosci. 2014 May;15(5):300-12
pubmed: 24713688
Arch Neurol. 1974 Sep;31(3):210-3
pubmed: 4368379
Nature. 1993 Feb 25;361(6414):726-30
pubmed: 8441467
N Engl J Med. 2017 Oct 26;377(17):1630-1638
pubmed: 28976817