PMID- 32997393 OWN - NLM STAT- MEDLINE DCOM- 20210924 LR - 20231108 IS - 2328-9503 (Electronic) IS - 2328-9503 (Linking) VI - 7 IP - 11 DP - 2020 Nov TI - Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275. PG - 2161-2177 LID - 10.1002/acn3.51200 [doi] AB - OBJECTIVE: 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). METHODS: 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. RESULTS: 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 LXRalpha/PPARgamma 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. INTERPRETATION: These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation. CI - (c) 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association. FAU - Zierfuss, Bettina AU - Zierfuss B AUID- ORCID: 0000-0002-5357-2630 AD - Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria. FAU - Weinhofer, Isabelle AU - Weinhofer I AUID- ORCID: 0000-0002-8455-2069 AD - Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria. FAU - Buda, Agnieszka AU - Buda A AUID- ORCID: 0000-0002-1996-3662 AD - Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria. FAU - Popitsch, Niko AU - Popitsch N AD - Institute of Molecular Biotechnology, Vienna, 1030, Austria. FAU - Hess, Lena AU - Hess L AD - Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, 1090, Austria. FAU - Moos, Verena AU - Moos V AD - Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, 1090, Austria. FAU - Hametner, Simon AU - Hametner S AD - Department of Neuropathology and Neurochemistry, Medical University of Vienna, Vienna, 1090, Austria. FAU - Kemp, Stephan AU - Kemp S AD - Laboratory Genetic Metabolic Diseases, Amsterdam UMC, Amsterdam Gastroenterology & Metabolism, Amsterdam Neuroscience, University of Amsterdam, Amsterdam, 1105AZ, The Netherlands. FAU - Kohler, Wolfgang AU - Kohler W AD - Department of Neurology, University of Leipzig Medical Centre, Leukodystrophy Clinic, Leipzig, 04103, Germany. FAU - Forss-Petter, Sonja AU - Forss-Petter S AD - Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria. FAU - Seiser, Christian AU - Seiser C AD - Division of Cell and Developmental Biology, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, 1090, Austria. FAU - Berger, Johannes AU - Berger J AUID- ORCID: 0000-0003-0182-2658 AD - Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria. LA - eng GR - DOC 33/FWF_/Austrian Science Fund FWF/Austria GR - P 28705/FWF_/Austrian Science Fund FWF/Austria PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20200930 PL - United States TA - Ann Clin Transl Neurol JT - Annals of clinical and translational neurology JID - 101623278 RN - 0 (Benzamides) RN - 0 (Histone Deacetylase Inhibitors) RN - 0 (Pyridines) RN - 1ZNY4FKK9H (entinostat) SB - IM MH - Acute Disease MH - *Adrenoleukodystrophy/drug therapy/immunology/metabolism MH - Adult MH - Autopsy MH - Benzamides/*pharmacology MH - Foam Cells/*drug effects MH - Gene Expression Profiling MH - Histone Deacetylase Inhibitors/*pharmacology MH - Humans MH - Immunohistochemistry MH - *Inflammation/drug therapy/immunology/metabolism MH - Middle Aged MH - *Multiple Sclerosis/drug therapy/immunology/metabolism MH - Pyridines/*pharmacology MH - Sequence Analysis, RNA MH - Young Adult PMC - PMC7664285 COIS- The authors declare no competing interests. EDAT- 2020/10/01 06:00 MHDA- 2021/09/25 06:00 PMCR- 2020/09/30 CRDT- 2020/09/30 12:18 PHST- 2020/07/08 00:00 [received] PHST- 2020/08/25 00:00 [revised] PHST- 2020/08/30 00:00 [accepted] PHST- 2020/10/01 06:00 [pubmed] PHST- 2021/09/25 06:00 [medline] PHST- 2020/09/30 12:18 [entrez] PHST- 2020/09/30 00:00 [pmc-release] AID - ACN351200 [pii] AID - 10.1002/acn3.51200 [doi] PST - ppublish SO - Ann Clin Transl Neurol. 2020 Nov;7(11):2161-2177. doi: 10.1002/acn3.51200. Epub 2020 Sep 30.