Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection

Roger, Thierry; Lugrin, Jérôme; Roy, Didier Le; Goy, Geneviève; Mombelli, Matteo; Koessler, Thibaud; Ding, Xavier C.; Chanson, Alain; Reymond, Marlies Knaup; Miconnet, Isabelle; Schrenzel, Jacques; François, Patrice; Calandra, Thierry

doi:10.1182/blood-2010-05-284711

Cited by 300 publications

(331 citation statements)

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“…Bacteria were grown to log phase in brain-heart infusion medium, washed, and resuspended in PBS at an OD 620 of 1.0. Whole blood from five healthy Caucasian subjects was drawn into S-monovette-tubes (Sarstedt) containing 16 U of heparin per mL, diluted fivefold in phenol red-free RPMI medium 1640 containing 2 mM L-glutamine (Life Technologies) (52). Blood was incubated at 37°C with S. pneumoniae (53).…”

Section: Methodsmentioning

confidence: 99%

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

Savva

Brouwer

Roger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Pneumococcal meningitis is the most frequent and critical type of bacterial meningitis. Because cytokines play an important role in the pathogenesis of bacterial meningitis, we examined whether functional polymorphisms of the proinflammatory cytokine macrophage migration inhibitory factor (MIF) were associated with morbidity and mortality of pneumococcal meningitis. Two functional MIF promoter polymorphisms, a microsatellite (−794 CATT 5-8 ; rs5844572) and a single-nucleotide polymorphism (−173 G/C; rs755622) were genotyped in a prospective, nationwide cohort of 405 patients with pneumococcal meningitis and in 329 controls matched for age, gender, and ethnicity. Carriages of the CATT 7 and −173 C high-expression MIF alleles were associated with unfavorable outcome (P = 0.005 and 0.003) and death (P = 0.03 and 0.01). In a multivariate logistic regression model, shock [odds ratio (OR) 26.0, P = 0.02] and carriage of the CATT 7 allele (OR 5.12, P = 0.04) were the main predictors of mortality. MIF levels in the cerebrospinal fluid were associated with systemic complications and death (P = 0.0002). Streptococcus pneumoniae strongly up-regulated MIF production in whole blood and transcription activity of high-expression MIF promoter Luciferase reporter constructs in THP-1 monocytes. Consistent with these findings, treatment with anti-MIF immunoglogulin G (IgG) antibodies reduced bacterial loads and improved survival in a mouse model of pneumococcal pneumonia and sepsis. The present study provides strong evidence that carriage of high-expression MIF alleles is a genetic marker of morbidity and mortality of pneumococcal meningitis and also suggests a potential role for MIF as a target of immune-modulating adjunctive therapy. macrophage migration inhibitory factor | polymorphism | meningitis | sepsis | innate immunity

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Section: Methodsmentioning

confidence: 99%

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

Savva

Brouwer

Roger

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…17,18 Other than chromatin proteins, transcription factors and cell-signaling regulatory proteins could also be the substrates for HDACs. 19 Particularly, HDAC superfamily has been receiving increasing attention for its role in modulating both innate and adaptive immune responses 20,21 implicatd in allograft survival and transplantation outcome. 22 As such, HDAC inhibitors (HDACis) are now under intensive study for their feasibility as potential anti-rejection agents.…”

Section: Introductionmentioning

confidence: 99%

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

et al. 2012

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Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA-and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-c but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4 1 T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORct in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.

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“…Small-molecule inhibitors of HDACs that have been developed as antican-cer agents (13) also reportedly have therapeutic effects in a range of inflammatory disease models (14). These anti-inflammatory effects likely result from the regulation of multiple immune cell types, including T regulatory cells (15), Th17 cells, (16), macrophages (17)(18)(19)(20), and dendritic cells (21). In macrophages, HDAC inhibitors reduce TLR-inducible production of a subset of proinflammatory cytokines, including TNF␣, IL-12, IL-6, chemokines such as monocyte chemoattractant proteins 1 and 3, and other inflammatory mediators, including endothelin 1 (ET-1) (17,18,20,22,23).…”

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confidence: 99%

“…These anti-inflammatory effects likely result from the regulation of multiple immune cell types, including T regulatory cells (15), Th17 cells, (16), macrophages (17)(18)(19)(20), and dendritic cells (21). In macrophages, HDAC inhibitors reduce TLR-inducible production of a subset of proinflammatory cytokines, including TNF␣, IL-12, IL-6, chemokines such as monocyte chemoattractant proteins 1 and 3, and other inflammatory mediators, including endothelin 1 (ET-1) (17,18,20,22,23). The mechanisms by which they do so remain poorly understood but may involve the impairment of transcription factor recruitment to target promoters (22) and inhibition of mitogen-activated protein kinase p38 signaling (10).…”

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confidence: 99%

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

Shakespear

Hohenhaus

Kelly

et al. 2013

Journal of Biological Chemistry

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Background: Histone deacetylase (HDAC) inhibitors reduce LPS-induced inflammatory mediator production from macrophages, but the relevant HDAC targets are unknown. Results: A specific isoform of Hdac7 amplifies expression of LPS-inducible genes via a HIF-1␣-dependent mechanism in macrophages. Conclusion:The class IIa HDAC Hdac7 promotes inflammatory responses in macrophages. Significance: Hdac7 may be a viable target for developing new anti-inflammatory drugs.

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Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection

Abstract: Regulated by histone acetyltransferases and deacetylases (HDACs), histone acetylation is a key epigenetic mechanism controlling chromatin structure, DNA accessibility, and gene expression.

Cited by 300 publications

References 50 publications

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

Functional polymorphisms of macrophage migration inhibitory factor as predictors of morbidity and mortality of pneumococcal meningitis

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

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

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