HDAC3 Mediates the Inflammatory Response and LPS Tolerance in Human Monocytes and Macrophages.
HDAC3 Mediates the Inflammatory Response and LPS Tolerance in Human Monocytes and Macrophages.
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DOI：
10.3389/fimmu.2020.550769
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发表时间：
2020
影响因子：
7.3
通讯作者：
de Jonge WJ
中科院分区：
文献类型：
--
作者：
Ghiboub M;Zhao J;Li Yim AYF;Schilderink R;Verseijden C;van Hamersveld PHP;Duarte JM;Hakvoort TBM;Admiraal I;Harker NR;Tough DF;Henneman P;de Winther MPJ;de Jonge WJ
组蛋白去乙酰化酶（hdac）是一组控制组蛋白去乙酰化的酶，具有指导大型基因集表达的潜力。我们确定了HDAC抑制剂（HDACi）对人类单核细胞和巨噬细胞的影响，包括它们的极化、激活和诱导内毒素耐受的能力。为了解决hdac在巨噬细胞极化中的作用，我们分别用IFNγ或IL-4在单核细胞极化为M1或M2巨噬细胞之前用HDAC3i、HDAC6i或pan-HDACi处理。为了研究HDAC对细胞因子表达的抑制作用，我们在lps刺激前用HDAC处理巨噬细胞。ELISA法检测TNFα、IL-6和p40， western blot法检测组蛋白3和STAT1的修饰。为了研究HDAC3在LPS诱导中的作用，在ifn - γ孵卵前将HDAC3i或HDAC3 siRNA添加到单核细胞中，然后用LPS重复激发，并通过蛋白质分析和转录谱分析进行分析。Pan-HDACi和HDAC3i可减少单核细胞和M1巨噬细胞的细胞因子分泌，而HDAC6i则无此作用。值得注意的是，pan-HDACi和HDAC3i都没有减少M2巨噬细胞的细胞因子分泌。与先前在小鼠巨噬细胞中的报道相反，HDAC3i不影响人细胞中的巨噬细胞极化。同样，HDAC3也不是IFNγ信号或IFNβ分泌所必需的。细胞因子和基因表达分析证实，ifn γ处理的巨噬细胞在LPS反复刺激后持续产生细胞因子反应，但HDAC3i或HDAC3 siRNA预处理可以恢复耐受状态，这可能是通过降低TLRs的表达，特别是TLR4/CD14的表达，从而抑制可耐受基因。巨噬细胞内毒素耐受性的发展对减轻免疫反应加剧和限制组织损伤至关重要。我们得出结论，HDAC3是介导炎性巨噬细胞反应性和耐受性诱导的一个有吸引力的蛋白靶点。
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.
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影响因子：
3.7
作者：
Foey AD;Crean S
通讯作者：
Crean S
影响因子：
4.4
作者：
Glauben, Rainer;Batra, Arvind;Siegmund, Britta
通讯作者：
Siegmund, Britta
影响因子：
64.8
作者：
Foster, Simmie L.;Hargreaves, Diana C.;Medzhitov, Ruslan
通讯作者：
Medzhitov, Ruslan
组蛋白脱乙酰基酶3调节类风湿关节炎成纤维细胞样的滑膜细胞的炎症基因表达程序。
影响因子：
27.4
作者：
Angiolilli C;Kabala PA;Grabiec AM;Van Baarsen IM;Ferguson BS;García S;Malvar Fernandez B;McKinsey TA;Tak PP;Fossati G;Mascagni P;Baeten DL;Reedquist KA
通讯作者：
Reedquist KA
DOI：
10.1038/nrg2485
发表时间：
2009-01
期刊：
Nature reviews. Genetics
影响因子：
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作者：
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