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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Pharmacol. | doi: 10.3389/fphar.2019.01242

Targeting histone deacetylases in myeloid cells inhibits their maturation and inflammatory function with limited effects on atherosclerosis

Rosario Luque Martin1,  Jan Van Den Bossche2*, Annette E. Neele3,  Rebecca C. Furze4, Saskia van der Velden3, Marion Gijbels3,  Cindy van Roomen3, Wouter J. de Jonge5,  Huw D. Lewis6,  Rab K. Prinjha6, Palwinder K. Mander6 and  Menno P. de Winther7*
  • 1Medical Biochemistry, University of Amsterdam, Netherlands
  • 2VU University Medical Center, Netherlands
  • 3Medical Biochemistry, University Medical Center Amsterdam, Netherlands
  • 4Epigenetics Research Unit (RU), GlaxoSmithKline (United Kingdom), United Kingdom
  • 5Tytgat Institute, University Medical Center Amsterdam, Netherlands
  • 6Epigenetics Research Unit, GlaxoSmithKline (United Kingdom), United Kingdom
  • 7Academic Medical Center (AMC), Netherlands

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 (iHDAC) 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 incorporates an esterase-sensitive motif (ESM) to small molecules to allow targeting of cells that express carboxylesterase 1 (CES1), such as mononuclear myeloid cells. In this study we utilised an HDAC inhibitor modified with the ESM-technology (ESM-iHDAC) 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-iHDAC did not significantly affect plaque size or phenotype, although histological classification of the plaques demonstrated a significant shift to a less severe phenotypes. We hereby show that HDAC inhibition in myeloid cells impairs the maturation and activation of peritoneal macrophages but only shows limited efficacy in a model of atherosclerosis.

Keywords: HDAC, Atherosclerosis, Therapeutic targeting, monocyte, Macrophage Maturation

Received: 26 Jun 2019; Accepted: 27 Sep 2019.

Copyright: © 2019 Luque Martin, Van Den Bossche, E. Neele, Furze, van der Velden, Gijbels, van Roomen, J. de Jonge, Lewis, Prinjha, Mander and de Winther. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Mx. Jan Van Den Bossche, VU University Medical Center, Amsterdam, Netherlands, j.vandenbossche@vumc.nl
Prof. Menno P. de Winther, Academic Medical Center (AMC), Amsterdam, 1105, Noord-Holland, Netherlands, m.dewinther@amsterdamumc.nl