Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Shakespear, Melanie R.; Hohenhaus, Daniel M.; Kelly, Gregory M.; Kamal, Nabilah A.; Gupta, Praveer; Labzin, Larisa I.; Schroder, Kate; Garceau, Valérie; Barbero, Sheila; Iyer, Abishek; Hume, David; Reid, Robert C.; Irvine, Katharine M.; Fairlie, David P.; Sweet, Matthew J.

doi:10.1074/jbc.m113.496281

Cited by 84 publications

(72 citation statements)

References 59 publications

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“…22 HDAC-7 could promote TLR4-dependent proinflammatory gene expression in macrophages. 15 Accordingly, HDAC inhibitor TSA could specifically inhibit LPSdependent gene expression in inflammatory macrophages 23 or epithelial cells. 24 TSA was also reported to suppress cell proliferation and epithelial-mesenchymal transition through inactivation of the component of LPS/TLR4 signaling pathway, such as phosphatidylinositol-3-kinase (PI3K)/Akt, p38 mitogen-activated protein kinase (MAPK), and extracellular signal-regulated kinase(ERK)1/2 pathways.…”

Section: Discussionmentioning

confidence: 99%

“…15 To test whether LPS/TLR4 promotes the proliferation of lung fibroblasts via HDACs, we determined the effect of LPS/TLR4 on HDAC-4, -5, and -7 expression and activation in lung fibroblasts. We infected lung fibroblasts with TLR4-siRNAlentivirus or treated cells with HDAC inhibitor TSA in the presence or absence of LPS challenge for different time points and assessed the HDAC-4, -5, and -7 mRNA and protein expression by real-time PCR and western blot, respectively.…”

Section: Silencing Of Tlr4 Inhibits Lps-enhanced Proliferation Of Lunmentioning

confidence: 99%

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HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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Lipopolysaccharide (LPS)-induced proliferation of lung fibroblasts is closely correlated with loss of gene expression of thymocyte differentiation antigen-1 (Thy-1), accompanied with deacetylation of histones H3 and H4 at the Thy-1 gene promoter region; however, the mechanism remains enigmatic. We report here that LPS downregulates Thy-1 gene expression by activating histone deacetylases (HDACs) via Toll-like receptor 4 (TLR4) signaling. Treatment of primary cultured mouse lung fibroblasts with LPS resulted in significant upregulation of TLR4 and enhanced cell proliferation that was abolished by silencing TLR4 with lentivirus-delivered TLR4 shRNA. Interestingly, LPS increased the mRNA and protein levels of HDAC-4, -5, and -7, an effect that was abrogated by HDAC inhibitor trichostatin A (TSA) or TLR4-shRNA-lentivirus. Consistent with these findings, Ace-H3 and Ace-H4 were decreased by LPS that was prevented by TSA. Most importantly, chromosome immunoprecipitation (ChIP) analysis demonstrated that LPS decreased the association of Ace-H4 at the Thy-1 promoter region that was efficiently restored by pretreatment with TSA. Accordingly, LPS decreased the mRNA and protein levels of Thy-1 that was inhibited by TSA. Furthermore, silencing the Thy-1 gene by lentivirus-delivered Thy-1 shRNA could promote lung fibroblast proliferation, even in the absence of LPS. Conversely, overexpressing Thy-1 gene could inhibit lung fibroblast proliferation and reduce LPS-induced lung fibroblast proliferation. Our data suggest that LPS upregulates and activates HDACs through TLR4, resulting in deacetylation of histones H3 and H4 at the Thy-1 gene promoter that may contribute to Thy-1 gene silencing and lung fibroblast proliferation. Pulmonary fibrosis is characterized by aberrant proliferation and activation of lung fibroblasts. 1,2 The phenotypic transition of lung fibroblasts during the process of pulmonary fibrosis can be stimulated by various pathological conditions, including lipopolysaccharide (LPS), a component of bacteria membranes and an important player during the development of pulmonary fibrosis. 3,4 LPS-induced proliferation of lung fibroblast is associated with the silencing of thymocyte differentiation antigen-1 (Thy-1) and deacetylation of histones H3 and H4 at the Thy-1 gene promoter; 5,6 however, the mechanism by which LPS promotes the deacetylation of histones H3 and H4 leading to downregulation of Thy-1 gene expression is largely unknown.Thy-1 is a cell surface glycoprotein that is present in normal lung fibroblasts but absent from the fibroblastic foci of idiopathic pulmonary fibrosis (IPF). 7 Heterogeneous surface expression of Thy-1 in fibroblasts results in the specialization of fibroblast, including Thy-1 (+) and Thy-1 (− ) subsets. Hagood et al 5,8,9 reported that lack of Thy-1 expression on lung fibroblasts contributed to IPF. Recently, it was found that epigenetic mechanisms, such as promoter hypermethylation and histone modification, play an important role in Thy-1 gene silencing in lung fibroblasts. 6,7 Our...

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Section: Discussionmentioning

confidence: 99%

Section: Silencing Of Tlr4 Inhibits Lps-enhanced Proliferation Of Lunmentioning

confidence: 99%

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Xing

Nie

et al. 2015

Laboratory Investigation

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“…Whereas M1 macrophages are pro-inflammatory and have a central role in atherosclerosis development and plaque rupture, M2 macrophages are associated with response to anti-inflammatory reactions, tissue remodeling, fibrosis and atherosclerosis regression 6 . Recent studies demonstrate that among HDACs, HDAC3 and HDAC7 have been identified to play a key role in inflammatory gene expression program and alternative activation of macrophages 7–9 . However, the role of HDAC9 in these processes in macrophages is unknown.…”

Section: Introductionmentioning

confidence: 99%

Histone Deacetylase 9 Represses Cholesterol Efflux and Alternatively Activated Macrophages in Atherosclerosis Development

Cao

Rong

Repa³

et al. 2014

ATVB

158

132

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Objective Recent genome-wide association studies revealed that a genetic variant in the loci corresponding to histone deacetylase 9 (HDAC9) is associated with large vessel stroke. HDAC9 expression was upregulated in human atherosclerotic plaques in different arteries. The molecular mechanisms how HDAC9 might increase atherosclerosis is not clear. Approach and Results In this study, we show that systemic and bone marrow cell deletion of HDAC9 decreased atherosclerosis in LDLr−/− mice with minimal effect on plasma lipid concentrations. HDAC9 deletion resulted upregulation of lipid homeostatic genes, downregulation of inflammatory genes, and polarization towards an M2 phenotype via increased accumulation of total acetylated H3 and H3K9 at the promoters of ABCA1, ABCG1, and PPAR-γ in macrophages. Conclusions We conclude that macrophage HDAC9 upregulation is atherogenic via suppression of cholesterol efflux and generation of alternatively activated macrophages in atherosclerosis.

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“…HDACi are reported to inhibit proinflammatory cytokine secretion via multiple mechanisms, including inhibiting the transcriptional activity of hypoxia-inducible factor 1-alpha (HIF-1␣) (8,11), impairing recruitment of proinflammatory transcription factors to target promoters (12), reducing the stability of mRNAs encoding inflammatory cytokines (13), and upregulating the expression and activity of the transcriptional repressor complex, Mi-2/NuRD (14). Such studies imply that certain HDACs have proinflammatory functions, and indeed this has been reported for a number of HDACs, for example, HDAC4 (15) and HDAC7 (11). As proinflammatory cytokines play important roles in host defense, it is a distinct possibility that HDACi may, in dampening inflammation, also compromise host defense.…”

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confidence: 99%

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

Ariffin

Gupta

Kapétanovic

et al. 2016

Antimicrob Agents Chemother

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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.

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Histone Deacetylase 7 Promotes Toll-like Receptor 4-dependent Proinflammatory Gene Expression in Macrophages

Cited by 84 publications

References 59 publications

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

HDAC is essential for epigenetic regulation of Thy-1 gene expression during LPS/TLR4-mediated proliferation of lung fibroblasts

Histone Deacetylase 9 Represses Cholesterol Efflux and Alternatively Activated Macrophages in Atherosclerosis Development

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

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