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Targeting foam cell formation in inflammatory brain diseases by the histone modifier MS-275
Bettina Zierfuss1, Isabelle Weinhofer1, Agnieszka Buda1
1Department of Pathobiology of the Nervous System, Centre for Brain Research, Medical University of Vienna, Vienna, 1090, Austria.
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.
Insights
Class I histone deacetylase (HDAC) inhibition reduces lipid accumulation in disease-promoting phagocytes. This strategy may prevent foam cell formation in neuroinflammatory disorders like multiple sclerosis (MS) and X-linked adrenoleukodystrophy (X-ALD).
Area of Science:
- Neuroimmunology and molecular mechanisms of neuroinflammation.
- Cellular biology of macrophages and foam cell formation.
- Biochemistry of histone deacetylases and lipid metabolism.
Background:
- Neuroinflammatory disorders such as multiple sclerosis (MS) and X-linked adrenoleukodystrophy (X-ALD) involve lipid-accumulating phagocytes.
- Foam cell formation, characterized by lipid accumulation, contributes to disease pathology in these conditions.
- Class I histone deacetylases (HDACs) play a role in cellular processes relevant to inflammation and metabolism.
Purpose of the Study:
- To investigate the effect of class I HDAC inhibition on the formation of lipid-laden, disease-promoting phagocytes.
- To assess the potential of class I HDAC inhibition as a therapeutic strategy for neuroinflammatory diseases.
- To analyze the impact of class I HDAC inhibition on myelin load-induced foam cell formation in vitro.
Main Methods:
- Analysis of postmortem brain tissue from MS and X-ALD patients to characterize phagocyte activation and foam cell state.
- RNA sequencing (RNA-Seq) of myelin-laden macrophages to identify metabolic shifts and gene expression changes.
- Treatment of human cells with a class I HDAC inhibitor (MS-275) and genetic manipulation (knockout/knock-in) of HDACs to assess effects on lipid accumulation and gene expression.
Main Results:
- Enlarged foam cells with a pro-inflammatory phenotype were observed in MS and X-ALD patient tissues.
- In vitro, MS-275 treatment amplified gene programs associated with tissue repair, reduced lipid/cholesterol accumulation, and inhibited foam cell formation.
- MS-275 improved very long-chain fatty acid (VLCFA) metabolism and reduced inflammation in X-ALD patient-derived macrophages.
Conclusions:
- Class I HDAC inhibition effectively reduces lipid accumulation and foam cell formation in relevant in vitro models.
- Targeting class I HDACs represents a potential novel therapeutic strategy for CNS inflammatory diseases.
- These findings offer a new avenue for preventing disease progression in conditions like MS and X-ALD.
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