Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis.

Rosario Luque-Martin,Wouter J De Jonge,Huw D Lewis,Jan Van Den Bossche,Inmaculada Rioja,Rab K Prinjha,Saskia Van Der Velden,Annette E Neele,Sharon G Bernard,Marion J.J Gijbels,Palwinder K Mander,Menno P.J De Winther,Rebecca C Furze,Cindy P.P.A Van Roomen

doi:10.3389/fphar.2019.01242

Abstract

Monocytes and macrophages are key drivers in the pathogenesis of inflammatory diseases. Epigenetic targets have been shown to control the transcriptional profile and phenotype of these cells. Since histone deacetylase protein inhibitors demonstrate profound anti-inflammatory activity, we wanted to test whether HDAC inhibition within monocytes and macrophages could be applied to suppress inflammation in vivo. ESM technology conjugates an esterase-sensitive motif (ESM) onto small molecules to allow targeting of cells that express carboxylesterase 1 (CES1), such as mononuclear myeloid cells. This study utilized an ESM-HDAC inhibitor to target monocytes and macrophages in mice in both an acute response model and an atherosclerosis model. We demonstrate that the molecule blocks the maturation of peritoneal macrophages and inhibits pro-inflammatory cytokine production in both models but to a lesser extent in the atherosclerosis model. Despite regulating the inflammatory response, ESM-HDAC528 did not significantly affect plaque size or phenotype, although histological classification of the plaques demonstrated a significant shift to a less severe phenotype. We hereby show that HDAC inhibition in myeloid cells impairs the maturation and activation of peritoneal macrophages but shows limited efficacy in a model of atherosclerosis.

Highlights

Emerging evidence suggests that epigenetics plays a crucial role in regulating immune cell function and may offer many potential therapeutic opportunities for immune-mediated inflammatory diseases
When the ester group is cleaved from the Histone deacetylases (HDAC) inhibitor, by the enzyme carboxylesterase 1 (CES1), in myeloid cells of the transgenic mice, it accumulates within those specific cells (Supplementary Figure 1A)
Macrophages play a role in virtually every stage of atherosclerosis and reshaping their dysregulated activation is considered to be the holy grail of macrophage therapeutic targeting (Sica and Mantovani, 2012)

Summary

Introduction

Emerging evidence suggests that epigenetics plays a crucial role in regulating immune cell function and may offer many potential therapeutic opportunities for immune-mediated inflammatory diseases. The identification of selective inhibitors of epigenetic enzymes and reader proteins has advanced our understanding of chromatin regulation of gene expression leading to renewed therapeutic efforts to reduce disease progression (Tough et al, 2016; Tough and Prinjha, 2017). Histone deacetylases (HDAC) are a family of proteins that remove acetyl groups from lysine residues on histone tails and other proteins. The removal of these acetyl groups from histones causes DNA to be more compact, leading to a decrease in gene expression. The classical inhibitors for these proteins broadly target classes I, II, and IV, which include 11 HDACs (New et al, 2012)

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Conclusion