Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275.

Abstract

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 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.

INTERPRETATION:

These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.

• Authors: Bettina Zierfuss, Isabelle Weinhofer, Agnieszka Buda, Niko Popitsch, Lena Hess, Verena Moos, Simon Hametner, Stephan Kemp, Wolfgang Köhler, Sonja Forss-Petter, Christian Seiser, Johannes Berger
• Journal: Annals of clinical and translational neurology (Ann Clin Transl Neurol) Vol. 7 Issue 11 Pg. 2161-2177 (11 2020) ISSN: 2328-9503 [Electronic] United States
• PMID: 32997393 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.

Chemical References

• Benzamides
• Histone Deacetylase Inhibitors
• Pyridines
• entinostat

Topics

• Acute Disease
• Adrenoleukodystrophy (drug therapy, immunology, metabolism)
• Adult
• Autopsy
• Benzamides (pharmacology)
• Foam Cells (drug effects)
• Gene Expression Profiling
• Histone Deacetylase Inhibitors (pharmacology)
• Humans
• Immunohistochemistry
• Inflammation (drug therapy, immunology, metabolism)
• Middle Aged
• Multiple Sclerosis (drug therapy, immunology, metabolism)
• Pyridines (pharmacology)
• Sequence Analysis, RNA
• Young Adult