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Biomolecules

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Efficacy of HDAC Inhibitors in Driving Peroxisomal β-Oxidation and Immune Responses in Human Macrophages: Implications for Neuroinflammatory Disorders

Published:23 November 2023 DOI: 10.3390/biom13121696 PMID: 38136568
Andrea Villoria-González,?Bettina Zierfuss,?Patricia Parzer,?Elisabeth Heub?ck,?Violetta Zujovic,?Petra Waidhofer-S?llner,?Markus Ponleitner,?Paulus Rommer,?Jens G?pfert,?Sonja Forss-Petter,?Johannes Berger,?Isabelle Weinhofer

Abstract

Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.

Substances (4)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Entinostat 209783-80-2 C21H20N4O3 277 suppliers $12.00-$1963.50
Entinostat 209783-80-2 C21H20N4O3 277 suppliers $12.00-$1963.50
Entinostat 209783-80-2 C21H20N4O3 277 suppliers $12.00-$1963.50
Entinostat 209783-80-2 C21H20N4O3 277 suppliers $12.00-$1963.50

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