Open AccessTargeting foam cell formation in inflammatory brain diseases by the histone modifier MS‐275
Author(s) -
Zierfuss Bettina,
Weinhofer Isabelle,
Buda Agnieszka,
Popitsch Niko,
Hess Lena,
Moos Verena,
Hametner Simon,
Kemp Stephan,
Köhler Wolfgang,
ForssPetter Sonja,
Seiser Christian,
Berger Johannes
Publication year - 2020
Publication title -
annals of clinical and translational neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.824
H-Index - 42
ISSN - 2328-9503
DOI - 10.1002/acn3.51200
Subject(s) - foam cell , myelin , lipid metabolism , multiple sclerosis , microglia , cell , medicine , inflammation , intracellular , in vitro , adrenoleukodystrophy , microbiology and biotechnology , cancer research , immunology , chemistry , biology , biochemistry , gene , macrophage , endocrinology , central nervous system , peroxisome
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 LXR α /PPAR γ 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.