Dataset Information

Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

ABSTRACT: Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism Mycobacterium tuberculosis (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune cells, glucose metabolism and its downsteam metabolic pathways generate key mediators which are essential co-substrates for post-translational modifications of histone proteins, which in turn, epigenetically regulate gene expression. Herein, we describe the role of sirtuins which are NAD⁺-dependent histone histone/protein deacetylases during the epigenetic regulation of autophagy, the production of ROS/RNS, acetyl-CoA, NAD⁺, and S-adenosine methionine (SAM), and illustrate the cross-talk between immunometabolism and epigenetics on macrophage activation. We highlight sirtuins as emerging therapeutic targets for modifying immunometabolism to alter macrophage phenotype and antimicrobial function.

SUBMITTER: Zhang K

PROVIDER: S-EPMC10040548 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

Zhang Kangling K Sowers Mark L ML Cherryhomes Ellie I EI Singh Vipul K VK Mishra Abhishek A Restrepo Blanca I BI Khan Arshad A Jagannath Chinnaswamy C

Frontiers in immunology 20230313

Macrophages are the preeminent phagocytic cells which control multiple infections. Tuberculosis a leading cause of death in mankind and the causative organism <i>Mycobacterium tuberculosis</i> (MTB) infects and persists in macrophages. Macrophages use reactive oxygen and nitrogen species (ROS/RNS) and autophagy to kill and degrade microbes including MTB. Glucose metabolism regulates the macrophage-mediated antimicrobial mechanisms. Whereas glucose is essential for the growth of cells in immune c ...[more]

PMID: 36993975

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Project description:Host-directed therapies aiming to strengthen the body's immune system, represent an underexplored opportunity to improve treatment of tuberculosis (TB). We have previously shown in Mycobacterium tuberculosis (Mtb)-infection models and clinical trials that treatment with the histone deacetylase (HDAC) inhibitor, phenylbutyrate (PBA), can restore Mtb-induced impairment of antimicrobial responses and improve clinical outcomes in pulmonary TB. In this study, we evaluated the efficacy of different groups of HDAC inhibitors to reduce Mtb growth in human immune cells. A panel of 21 selected HDAC inhibitors with different specificities that are known to modulate infection or inflammation was tested using high-content live-cell imaging and analysis. Monocyte-derived macrophages or bulk peripheral blood cells (PBMCs) were infected with the green fluorescent protein (GFP)-expressing Mtb strains H37Ra or H37Rv and treated with HDAC inhibitors in the micromolar range in parallel with a combination of the first-line antibiotics, rifampicin, and isoniazid. Host cell viability in HDAC inhibitor treated cell cultures was monitored with Cytotox-red. Seven HDAC inhibitors were identified that reduced Mtb growth in macrophages > 45-75% compared to average 40% for PBA. The most effective compounds were inhibitors of the class III HDAC proteins, the sirtuins. While these compounds may exhibit their effects by improving macrophage function, one of the sirtuin inhibitors, tenovin, was also highly effective in extracellular killing of Mtb bacilli. Antimicrobial synergy testing using checkerboard assays revealed additive effects between selected sirtuin inhibitors and subinhibitory concentrations of rifampicin or isoniazid. A customized macrophage RNA array including 23 genes associated with cytokines, chemokines and inflammation, suggested that Mtb-infected macrophages are differentially modulated by the sirtuin inhibitors as compared to PBA. Altogether, these results demonstrated that sirtuin inhibitors may be further explored as promising host-directed compounds to support immune functions and reduce intracellular growth of Mtb in human cells.

Dataset Information

Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

Publications

Sirtuin-dependent metabolic and epigenetic regulation of macrophages during tuberculosis.

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