Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages

被引:41
作者
Ariffin, Juliana K.
das Gupta, Kaustav
Kapetanovic, Ronan
Iyer, Abishek
Reid, Robert C.
Fairlie, David P.
Sweet, Matthew J. [1 ]
机构
[1] Univ Queensland, Inst Mol Biosci, IMB Ctr Inflammat & Dis Res, Brisbane, Qld, Australia
基金
澳大利亚国家健康与医学研究理事会; 澳大利亚研究理事会; 英国医学研究理事会;
关键词
PROINFLAMMATORY GENE-EXPRESSION; RHEUMATOID-ARTHRITIS; HDAC INHIBITORS; SERIOUS INFECTIONS; MOUSE; SURVIVAL; THERAPY; CONSERVATION; ACETYLATION; DIVERGENCE;
D O I
10.1128/AAC.01876-15
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
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.
引用
收藏
页码:1521 / 1529
页数:9
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