HDAC3 Mediates the Inflammatory Response and LPS Tolerance in Human Monocytes and Macrophages
Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabil...
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| Veröffentlicht in: | Frontiers in immunology Jg. 11; S. 550769 |
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| Abstract | Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or
siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or
siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages. |
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| AbstractList | Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or HDAC3 siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or HDAC3 siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages. Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages. Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or HDAC3 siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or HDAC3 siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages.Histone deacetylases (HDACs) are a group of enzymes that control histone deacetylation and bear potential to direct expression of large gene sets. We determined the effect of HDAC inhibitors (HDACi) on human monocytes and macrophages, with respect to their polarization, activation, and their capabilities of inducing endotoxin tolerance. To address the role for HDACs in macrophage polarization, we treated monocytes with HDAC3i, HDAC6i or pan-HDACi prior to polarization into M1 or M2 macrophages using IFNγ or IL-4 respectively. To study the HDAC inhibition effect on cytokine expression, macrophages were treated with HDACi prior to LPS-stimulation. TNFα, IL-6, and p40 were measured with ELISA, whereas modifications of Histone 3 and STAT1 were assessed using western blot. To address the role for HDAC3 in repeated LPS challenge induction, HDAC3i or HDAC3 siRNA was added to monocytes prior to incubation with IFNγ, which were then repeatedly challenged with LPS and analyzed by means of protein analyses and transcriptional profiling. Pan-HDACi and HDAC3i reduced cytokine secretion in monocytes and M1 macrophages, whereas HDAC6i yielded no such effect. Notably, neither pan-HDACi nor HDAC3i reduced cytokine secretion in M2 macrophages. In contrast to previous reports in mouse macrophages, HDAC3i did not affect macrophage polarization in human cells. Likewise, HDAC3 was not required for IFNγ signaling or IFNβ secretion. Cytokine and gene expression analyses confirmed that IFNγ-treated macrophages consistently develop a cytokine response after LPS repeated challenge, but pretreatment with HDAC3i or HDAC3 siRNA reinstates a state of tolerance reflected by general suppression of tolerizable genes, possibly through decreasing TLRs expression, and particularly TLR4/CD14. The development of endotoxin tolerance in macrophages is important to reduce exacerbated immune response and limit tissue damage. We conclude that HDAC3 is an attractive protein target to mediate macrophage reactivity and tolerance induction in inflammatory macrophages. |
| Author | Duarte, Jose M. Schilderink, Ronald Harker, Nicola R. de Jonge, Wouter J. Verseijden, Caroline Henneman, Peter van Hamersveld, Patricia H. P. Hakvoort, Theodorus B. M. Zhao, Jing de Winther, Menno P. J. Li Yim, Andrew Y. F. Tough, David F. Ghiboub, Mohammed Admiraal, Iris |
| AuthorAffiliation | 3 Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam , Amsterdam , Netherlands 5 Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam , Amsterdam , Netherlands 7 Department of Surgery, University of Bonn , Bonn , Germany 1 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, University of Amsterdam , Amsterdam , Netherlands 6 Department of Medicine, Institute for Cardiovascular Prevention (IPEK) , Munich , Germany 4 Adaptive Immunity Research Unit, Medicines Research Centre, GlaxoSmithKline , Stevenage , United Kingdom 2 Epigenetics Discovery Performance Unit, Immunoinflammation Therapy Area Unit, Medicines Research Centre, GlaxoSmithKline , Stevenage , United Kingdom |
| AuthorAffiliation_xml | – name: 3 Genome Diagnostics Laboratory, Amsterdam Reproduction & Development, Department of Clinical Genetics, Amsterdam University Medical Centers, University of Amsterdam , Amsterdam , Netherlands – name: 5 Department of Medical Biochemistry, Amsterdam University Medical Centers, University of Amsterdam , Amsterdam , Netherlands – name: 6 Department of Medicine, Institute for Cardiovascular Prevention (IPEK) , Munich , Germany – name: 4 Adaptive Immunity Research Unit, Medicines Research Centre, GlaxoSmithKline , Stevenage , United Kingdom – name: 1 Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology & Metabolism, Amsterdam University Medical Centers, University of Amsterdam , Amsterdam , Netherlands – name: 2 Epigenetics Discovery Performance Unit, Immunoinflammation Therapy Area Unit, Medicines Research Centre, GlaxoSmithKline , Stevenage , United Kingdom – name: 7 Department of Surgery, University of Bonn , Bonn , Germany |
| Author_xml | – sequence: 1 givenname: Mohammed surname: Ghiboub fullname: Ghiboub, Mohammed – sequence: 2 givenname: Jing surname: Zhao fullname: Zhao, Jing – sequence: 3 givenname: Andrew Y. F. surname: Li Yim fullname: Li Yim, Andrew Y. F. – sequence: 4 givenname: Ronald surname: Schilderink fullname: Schilderink, Ronald – sequence: 5 givenname: Caroline surname: Verseijden fullname: Verseijden, Caroline – sequence: 6 givenname: Patricia H. P. surname: van Hamersveld fullname: van Hamersveld, Patricia H. P. – sequence: 7 givenname: Jose M. surname: Duarte fullname: Duarte, Jose M. – sequence: 8 givenname: Theodorus B. M. surname: Hakvoort fullname: Hakvoort, Theodorus B. M. – sequence: 9 givenname: Iris surname: Admiraal fullname: Admiraal, Iris – sequence: 10 givenname: Nicola R. surname: Harker fullname: Harker, Nicola R. – sequence: 11 givenname: David F. surname: Tough fullname: Tough, David F. – sequence: 12 givenname: Peter surname: Henneman fullname: Henneman, Peter – sequence: 13 givenname: Menno P. J. surname: de Winther fullname: de Winther, Menno P. J. – sequence: 14 givenname: Wouter J. surname: de Jonge fullname: de Jonge, Wouter J. |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33123128$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright © 2020 Ghiboub, Zhao, Li Yim, Schilderink, Verseijden, van Hamersveld, Duarte, Hakvoort, Admiraal, Harker, Tough, Henneman, de Winther and de Jonge. Copyright © 2020 Ghiboub, Zhao, Li Yim, Schilderink, Verseijden, van Hamersveld, Duarte, Hakvoort, Admiraal, Harker, Tough, Henneman, de Winther and de Jonge 2020 Ghiboub, Zhao, Li Yim, Schilderink, Verseijden, van Hamersveld, Duarte, Hakvoort, Admiraal, Harker, Tough, Henneman, de Winther and de Jonge |
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| Keywords | IFNγ HDAC3 inhibition inflammatory response macrophages LPS tolerance |
| Language | English |
| License | Copyright © 2020 Ghiboub, Zhao, Li Yim, Schilderink, Verseijden, van Hamersveld, Duarte, Hakvoort, Admiraal, Harker, Tough, Henneman, de Winther and de Jonge. 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. |
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| Notes | ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Edited by: Jan Fric, International Clinical Research Center (FNUSA-ICRC), Czechia This article was submitted to Molecular Innate Immunity, a section of the journal Frontiers in Immunology These authors have contributed equally to this work Reviewed by: Diana Boraschi, Istituto di biochimica delle proteine (IBP), Italy; Ulisses Gazos Lopes, Federal University of Rio de Janeiro, Brazil |
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| SubjectTerms | Cytokines - genetics Cytokines - metabolism Enzyme Activation Gene Expression HDAC3 inhibition Histone Deacetylase Inhibitors - pharmacology Histone Deacetylases - genetics Histone Deacetylases - metabolism Humans IFNγ Immune Tolerance - drug effects Immunology Immunophenotyping Inflammation - drug therapy Inflammation - etiology Inflammation - metabolism Inflammation - pathology inflammatory response Lipopolysaccharides - immunology LPS tolerance Macrophage Activation - drug effects Macrophage Activation - immunology macrophages Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Monocytes - drug effects Monocytes - immunology Monocytes - metabolism Protein Binding |
| Title | HDAC3 Mediates the Inflammatory Response and LPS Tolerance in Human Monocytes and Macrophages |
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