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
Hauptverfasser: Ghiboub, Mohammed, Zhao, Jing, Li Yim, Andrew Y. F., Schilderink, Ronald, Verseijden, Caroline, van Hamersveld, Patricia H. P., Duarte, Jose M., Hakvoort, Theodorus B. M., Admiraal, Iris, Harker, Nicola R., Tough, David F., Henneman, Peter, de Winther, Menno P. J., de Jonge, Wouter J.
Format: Journal Article
Sprache:Englisch
Veröffentlicht: Switzerland Frontiers Media S.A 05.10.2020
Schlagworte:
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
IFNγ
HDAC3 inhibition
inflammatory response
macrophages
LPS tolerance
ISSN:1664-3224, 1664-3224
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Zusammenfassung: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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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
ISSN:1664-3224
1664-3224
DOI:10.3389/fimmu.2020.550769