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

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.

Cell-specific epigenetic changes in atherosclerosis

“…The HDACs SIRT1 and SIRT 6, on the other hand have been shown to enhance cholesterol efflux by the activation of ABCA1 and ABCG1 blunting formation of foam cells and associated inflammation [82]. Recently, myeloid-specific HDAC inhibition using an esterase-sensitive motif (ESM) technology has been shown to impair maturation and activation of peritoneal macrophages with limited efficacy on atherosclerosis [83]. This technology conjugates ESM on to small molecules for targeting those cells that express Carboxylesterase 1 (CES1), such as mononuclear myeloid cells [83].…”

Selective Targeting of Epigenetic Readers and Histone Deacetylases in Autoimmune and Inflammatory Diseases: Recent Advances and Future Perspectives

“…This sparked the interest to further explore this strategy in other inflammatory disease models. In both acute DSS colitis [ 116 ] and acute peritonitis [ 117 ] models, ESM-HDACi impaired the differentiation of monocyte in inflamed tissue, which translated into modestly improved colitis [ 116 ]. Exploring this strategy in a variety of inflammatory disease models may identify the best application of this approach given the complex role of these cells in mediating the inflammatory response in different diseases [ 118 , 119 ].…”

Preclinical and clinical progress for HDAC as a putative target for epigenetic remodeling and functionality of immune cells

“…One attractive approach for atherosclerosis therapy is to target macrophage-mediated inflammation. EMconjugated HDACi, which specifically targets cells expressing carboxylesterase-1, such as monocytes and macrophages, limited peritoneal macrophage maturation but had no inhibitory effect on bone marrow-derived macrophages from WT mice; however, it showed limited efficacy in an atherosclerosis model, [97]. In the acute myocardial infarction mouse model, SAHA upregulated M2 markers, thereby facilitating ventricular remodeling and functional recovery [98].…”