Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish

Moreira, Jôsimar Dornelas; Koch, Bjørn E. V.; Veen, Sylvia; Walburg, Kimberley V.; Vrieling, Frank; Guimarães, Talita Antunes; Meijer, Annemarie H.; Spaink, Herman P.; Ottenhoff, Tom H. M.; Haks, Mariëlle C.; Heemskerk, Matthias T.

doi:10.3389/fimmu.2020.00036

Cited by 46 publications

(58 citation statements)

References 89 publications

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“…We recently demonstrated in vivo efficacy of this approach, using inhaled macrophage homing micro-particles that contain all-trans retinoic acid which drives macrophage anti-TB responses ( 72 , 73 ). Targeting HDACs has previously been postulated to have potential as an adjunct host-directed therapy for TB ( 10 , 74 ). Our data is also supported by published in vivo data showing that Tubastatin A, a selective HDAC6 inhibitor, reduced IL-10, and enhanced Th1 responses in mice infected with Mtb H37Ra ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

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Inhibiting Histone Deacetylases in Human Macrophages Promotes Glycolysis, IL-1β, and T Helper Cell Responses to Mycobacterium tuberculosis

et al. 2020

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Tuberculosis (TB) is the leading infectious killer in the world. Mycobacterium tuberculosis (Mtb), the bacteria that causes the disease, is phagocytosed by alveolar macrophages (AM) and infiltrating monocyte-derived macrophages (MDM) in the lung. Infected macrophages then upregulate effector functions through epigenetic modifications to make DNA accessible for transcription. The metabolic switch to glycolysis and the production of proinflammatory cytokines are key effector functions, governed by epigenetic changes, that are integral to the ability of the macrophage to mount an effective immune response against Mtb. We hypothesised that suberanilohydroxamic acid (SAHA), an FDA-approved histone deacetylase inhibitor (HDACi), can modulate epigenetic changes upstream of the metabolic switch and support immune responses during Mtb infection. The rate of glycolysis in human MDM, infected with Mtb and treated with SAHA, was tracked in real time on the Seahorse XFe24 Analyzer. SAHA promoted glycolysis early in the response to Mtb. This was associated with significantly increased production of IL-1β and significantly reduced IL-10 in human MDM and AM. Since innate immune function directs downstream adaptive immune responses, we used SAHA-treated Mtb-infected AM or MDM in a co-culture system to stimulate T cells. Mtb-infected macrophages that had previously been treated with SAHA promoted IFN-γ, GM-CSF, and TNF co-production in responding T helper cells but did not affect cytotoxic T cells. These results indicate that SAHA promoted the early switch to glycolysis, increased IL-1β, and reduced IL-10 production in human macrophages infected with Mtb. Moreover, the elevated proinflammatory function of SAHA-treated macrophages resulted in enhanced T helper cell cytokine polyfunctionality. These data provide an in vitro proof-of-concept for the use of HDACi to modulate human immunometabolic processes in macrophages to promote innate and subsequent adaptive proinflammatory responses.

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Section: Discussionmentioning

confidence: 99%

“…Mtb infection can target host HDAC to modulate the immune response ( 7 , 8 ). In keeping, HDAC inhibitors (HDACi) are being explored for their ability to modulate the development of TB ( 3 , 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Inhibiting Histone Deacetylases in Human Macrophages Promotes Glycolysis, IL-1β, and T Helper Cell Responses to Mycobacterium tuberculosis

et al. 2020

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“…It has been shown that Mtb inhibits the expression of IFNγ-induced genes including CIITA, CD64, and HLA-DR through histone deacetylation ( Kincaid and Ernst, 2003 ; Wang et al, 2005 ). Moreover, broad-spectrum HDAC inhibitors enhance the anti-mycobacterial potential of host cells ( Moreira et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Host sirtuin 2 as an immunotherapeutic target against tuberculosis

Bhaskar

Kumar

Khan

et al. 2020

eLife

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Mycobacterium tuberculosis (Mtb) employs plethora of mechanisms to hijack the host defence machinery for its successful survival, proliferation and persistence. Here, we show that Mtb upregulates one of the key epigenetic modulators, NAD+ dependent histone deacetylase Sirtuin 2 (SIRT2), which upon infection translocate to the nucleus and deacetylates histone H3K18, thus modulating the host transcriptome leading to enhanced macrophage activation. Furthermore, in Mtb specific T cells, SIRT2 deacetylates NFκB-p65 at K310 to modulate T helper cell differentiation. Pharmacological inhibition of SIRT2 restricts the intracellular growth of both drug-sensitive and resistant strains of Mtb and enhances the efficacy of front line anti-TB drug Isoniazid in the murine model of infection. SIRT2 inhibitor-treated mice display reduced bacillary load, decreased disease pathology and increased Mtb-specific protective immune responses. Overall, this study provides a link between Mtb infection, epigenetics and host immune response, which can be exploited to achieve therapeutic benefits.

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“…HDAC6 inhibitor Tubustatin A has been shown to reduce MTB survival in an in vivo mouse model (Wang et al, 2018). The pan-HDAC inhibitor trichostatin A and class IIa HDAC inhibitor TMP195 have been shown to be very effective in reducing MTB infection in primary human macrophages, and Mycobacterium marinum infection in zebrafish model (Moreira et al, 2020). Rao et al (2018) evaluated the possibility of the histone deacetylase inhibitors valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) to enhance the activity of first-line anti-TB drugs to inhibit the growth of intracellular MTB.…”

Section: Discussionmentioning

confidence: 99%

Transcription repressor protein ZBTB25 interacts with HDAC1 in macrophages infected withMycobacterium tuberculosis,and its inhibition leads to autophagy and killing of the intracellular pathogen

Madhavan

Arun

Pushparajan

et al. 2020

Preprint

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Downregulation of host gene expression is one of the key strategies adopted by intracellular pathogens such as Mycobacterium tuberculosis (MTB) for their survival and subsequent pathogenesis. In a previous study, we have shown that HDAC1 levels go up in macrophages infected with MTB and it hypoacetylates histone H3 at the promoter of IL-12B gene leading to its downregulation. Here we show that after infection with MTB, the levels of the phosphorylated form of HDAC1 increase significantly in macrophages. Employing immunoprecipitation and LC-MS/MS, we found transcriptional repressor protein ZBTB25 associates with HDAC1 silencing complex along with transcriptional corepressor Sin3a. By chromatin immunoprecipitation and PCR analyses, we found that phosphorylated HDAC1, Sin3a, and ZBTB25 are recruited to the promoter of IL-12B to downregulate its expression in infected macrophages. Knocking down of ZBTB25 enhanced release of IL-12p40 from infected macrophages. Interestingly, the treatment of infected macrophages with CI994 (inhibitor of HDAC1) or dithiopyridine (inhibitor of ZBTB25) promoted the colocalization of LC3 (microtubule-associated protein 1A/1B-light chain 3, a marker for autophagy) and MTB in autophagosomes. Induction of autophagy resulted in the killing of intracellular MTB.Enhanced phosphorylation of JAK2 and STAT4 was observed in macrophages upon CI994 and dithiopyridine treatment, and inhibition of JAK2/STAT4 negated the killing of intracellular mycobacteria suggesting a possible role of these proteins in the autophagymediated killing of intracellular MTB.

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Functional Inhibition of Host Histone Deacetylases (HDACs) Enhances in vitro and in vivo Anti-mycobacterial Activity in Human Macrophages and in Zebrafish

Cited by 46 publications

References 89 publications

Inhibiting Histone Deacetylases in Human Macrophages Promotes Glycolysis, IL-1β, and T Helper Cell Responses to Mycobacterium tuberculosis

Inhibiting Histone Deacetylases in Human Macrophages Promotes Glycolysis, IL-1β, and T Helper Cell Responses to Mycobacterium tuberculosis

Host sirtuin 2 as an immunotherapeutic target against tuberculosis

Transcription repressor protein ZBTB25 interacts with HDAC1 in macrophages infected withMycobacterium tuberculosis,and its inhibition leads to autophagy and killing of the intracellular pathogen

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