Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis
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 t...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-10-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fphar.2019.01242/full |
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| author | Rosario Luque-Martin Jan Van den Bossche Rebecca C. Furze Annette E. Neele Saskia van der Velden Marion J.J. Gijbels Marion J.J. Gijbels Cindy P.P.A. van Roomen Sharon G. Bernard Wouter J. de Jonge Inmaculada Rioja Rab K. Prinjha Huw D. Lewis Palwinder K. Mander Menno P.J. de Winther Menno P.J. de Winther |
| author_facet | Rosario Luque-Martin Jan Van den Bossche Rebecca C. Furze Annette E. Neele Saskia van der Velden Marion J.J. Gijbels Marion J.J. Gijbels Cindy P.P.A. van Roomen Sharon G. Bernard Wouter J. de Jonge Inmaculada Rioja Rab K. Prinjha Huw D. Lewis Palwinder K. Mander Menno P.J. de Winther Menno P.J. de Winther |
| author_sort | Rosario Luque-Martin |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T08:25:51Z |
| format | Article |
| id | doaj.art-0bd1c20ec87342d695539812e636ba12 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-19T08:25:51Z |
| publishDate | 2019-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-0bd1c20ec87342d695539812e636ba122022-12-21T20:29:18ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122019-10-011010.3389/fphar.2019.01242481104Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on AtherosclerosisRosario Luque-Martin0Jan Van den Bossche1Rebecca C. Furze2Annette E. Neele3Saskia van der Velden4Marion J.J. Gijbels5Marion J.J. Gijbels6Cindy P.P.A. van Roomen7Sharon G. Bernard8Wouter J. de Jonge9Inmaculada Rioja10Rab K. Prinjha11Huw D. Lewis12Palwinder K. Mander13Menno P.J. de Winther14Menno P.J. de Winther15Department of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsAmsterdam UMC, Vrije Universiteit Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Cardiovascular Sciences, Cancer Center Amsterdam, Amsterdam, NetherlandsImmuno-Epigenetics, Adaptive Immunity Research Unit, GSK Medicines Research Centre, Stevenage, United KingdomDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsDepartment of Pathology and Department of Molecular Genetics, CARIM, University Maastricht, Maastricht, NetherlandsDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsImmuno-Epigenetics, Adaptive Immunity Research Unit, GSK Medicines Research Centre, Stevenage, United KingdomTygat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsImmuno-Epigenetics, Adaptive Immunity Research Unit, GSK Medicines Research Centre, Stevenage, United KingdomImmuno-Epigenetics, Adaptive Immunity Research Unit, GSK Medicines Research Centre, Stevenage, United KingdomImmuno-Epigenetics, Adaptive Immunity Research Unit, GSK Medicines Research Centre, Stevenage, United KingdomImmuno-Epigenetics, Adaptive Immunity Research Unit, GSK Medicines Research Centre, Stevenage, United KingdomDepartment of Medical Biochemistry, Experimental Vascular Biology, Amsterdam Cardiovascular Sciences, Amsterdam UMC, University of Amsterdam, Amsterdam, NetherlandsInstitute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University, Munich, GermanyMonocytes 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.https://www.frontiersin.org/article/10.3389/fphar.2019.01242/fullhistone deacetylaseatherosclerosistherapeutic targetingmonocytemacrophage maturation |
| spellingShingle | Rosario Luque-Martin Jan Van den Bossche Rebecca C. Furze Annette E. Neele Saskia van der Velden Marion J.J. Gijbels Marion J.J. Gijbels Cindy P.P.A. van Roomen Sharon G. Bernard Wouter J. de Jonge Inmaculada Rioja Rab K. Prinjha Huw D. Lewis Palwinder K. Mander Menno P.J. de Winther Menno P.J. de Winther Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis Frontiers in Pharmacology histone deacetylase atherosclerosis therapeutic targeting monocyte macrophage maturation |
| title | Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis |
| title_full | Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis |
| title_fullStr | Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis |
| title_full_unstemmed | Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis |
| title_short | Targeting Histone Deacetylases in Myeloid Cells Inhibits Their Maturation and Inflammatory Function With Limited Effects on Atherosclerosis |
| title_sort | targeting histone deacetylases in myeloid cells inhibits their maturation and inflammatory function with limited effects on atherosclerosis |
| topic | histone deacetylase atherosclerosis therapeutic targeting monocyte macrophage maturation |
| url | https://www.frontiersin.org/article/10.3389/fphar.2019.01242/full |
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