title: Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages.
abstract: Broad-spectrum histone deacetylase inhibitors (HDACi) are used clinically as anticancer agents, and more isoform-selective HDACi have been sought to modulate other conditions, including chronic inflammatory diseases. Mouse studies suggest that HDACi downregulate immune responses and may compromise host defense. However, their effects on human macrophage antimicrobial responses are largely unknown. Here, we show that overnight pretreatment of human macrophages with HDACi prior to challenge with Salmonella enterica serovar Typhimurium or Escherichia coli results in significantly reduced intramacrophage bacterial loads, which likely reflect the fact that this treatment regime impairs phagocytosis. In contrast, cotreatment of human macrophages with HDACi at the time of bacterial challenge did not impair phagocytosis; instead, HDACi cotreatment actually promoted clearance of intracellular S. Typhimurium and E. coli. Mechanistically, treatment of human macrophages with HDACi at the time of bacterial infection enhanced mitochondrial reactive oxygen species generation by these cells. The capacity of HDACi to promote the clearance of intracellular bacteria from human macrophages was abrogated when cells were pretreated with MitoTracker Red CMXRos, which perturbs mitochondrial function. The HDAC6-selective inhibitor tubastatin A promoted bacterial clearance from human macrophages, whereas the class I HDAC inhibitor MS-275, which inhibits HDAC1 to -3, had no effect on intracellular bacterial loads. These data are consistent with HDAC6 and/or related HDACs constraining mitochondrial reactive oxygen species production from human macrophages during bacterial challenge. Our findings suggest that, whereas long-term HDACi treatment regimes may potentially compromise host defense, selective HDAC inhibitors may have applications in treating acute bacterial infections.
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Juliana K
authors.initials: JK
authors.lastname: Ariffin
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Kaustav
authors.initials: K
authors.lastname: das Gupta
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Ronan
authors.initials: R
authors.lastname: Kapetanovic
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Abishek
authors.initials: A
authors.lastname: Iyer
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Robert C
authors.initials: RC
authors.lastname: Reid
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: David P
authors.initials: DP
authors.lastname: Fairlie
authors.affiliation: Institute for Molecular Bioscience, IMB Centre for Inflammation and Disease Research and Australian Infectious Diseases Research Centre, The University of Queensland, Brisbane, Queensland, Australia m.sweet@imb.uq.edu.au.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Sweet
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D058491:Bacterial Load / Q000187:drug effects; D001549:Benzamides / Q000494:pharmacology; D002478:Cells, Cultured; D004926:Escherichia coli / Q000276:immunology*; D000073864:Histone Deacetylase 6; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D007211:Indoles / Q000494:pharmacology; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008928:Mitochondria / Q000276:immunology*; D009930:Organic Chemicals / Q000494:pharmacology; D010587:Phagocytosis / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism*; D012486:Salmonella typhimurium / Q000276:immunology*
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; D007211:Indoles; D009930:Organic Chemicals; D011725:Pyridines; D017382:Reactive Oxygen Species; C107472:red dye CMXRos; C118739:entinostat; C553587:tubastatin A; C433811:HDAC6 protein, human; D000073864:Histone Deacetylase 6; D006655:Histone Deacetylases