11 results on '"Kaustav Das Gupta"'
Search Results
2. Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2
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Kaustav Das Gupta, Melanie R. Shakespear, James E.B. Curson, Ambika M.V. Murthy, Abishek Iyer, Mark P. Hodson, Divya Ramnath, Vikas A. Tillu, Jessica B. von Pein, Robert C. Reid, Kathryn Tunny, Daniel M. Hohenhaus, Shayli Varasteh Moradi, Gregory M. Kelly, Takumi Kobayashi, Jennifer H. Gunter, Alexander J. Stevenson, Weijun Xu, Lin Luo, Alun Jones, Wayne A. Johnston, Antje Blumenthal, Kirill Alexandrov, Brett M. Collins, Jennifer L. Stow, David P. Fairlie, and Matthew J. Sweet
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Biology (General) ,QH301-705.5 - Abstract
Summary: Histone deacetylases (HDACs) drive innate immune cell-mediated inflammation. Here we identify class IIa HDACs as key molecular links between Toll-like receptor (TLR)-inducible aerobic glycolysis and macrophage inflammatory responses. A proteomic screen identified the glycolytic enzyme pyruvate kinase M isoform 2 (Pkm2) as a partner of proinflammatory Hdac7 in murine macrophages. Myeloid-specific Hdac7 overexpression in transgenic mice amplifies lipopolysaccharide (LPS)-inducible lactate and promotes a glycolysis-associated inflammatory signature. Conversely, pharmacological or genetic targeting of Hdac7 and other class IIa HDACs attenuates LPS-inducible glycolysis and accompanying inflammatory responses in macrophages. We show that an Hdac7-Pkm2 complex acts as an immunometabolism signaling hub, whereby Pkm2 deacetylation at lysine 433 licenses its proinflammatory functions. Disrupting this complex suppresses inflammatory responses in vitro and in vivo. Class IIa HDACs are thus pivotal intermediates connecting TLR-inducible glycolysis to inflammation via Pkm2. : Das Gupta et al. show that HDAC7 and other class IIa HDAC enzymes control macrophage metabolism. They initiate TLR-inducible glycolysis in these cells and interact with the glycolytic enzyme PKM2 to drive inflammatory responses in vitro and in vivo. Class IIa HDAC inhibitors may have potential for attenuating immunometabolism-linked inflammation. Keywords: glycolysis, histone deacetylases, immunometabolism, inflammation, lysine acetylation, macrophage, post-translational modification, pyruvate kinase, toll-like receptor
- Published
- 2020
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3. HDAC7 is an immunometabolic switch triaging danger signals for engagement of antimicrobial versus inflammatory responses in macrophages
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Kaustav Das Gupta, Divya Ramnath, Jessica B. von Pein, James E. B. Curson, Yizhuo Wang, Rishika Abrol, Asha Kakkanat, Shayli Varasteh Moradi, Kimberley S. Gunther, Ambika M. V. Murthy, Claudia J. Stocks, Ronan Kapetanovic, Robert C. Reid, Abishek Iyer, Zoe C. Ilka, William M. Nauseef, Manuel Plan, Lin Luo, Jennifer L. Stow, Kate Schroder, Denuja Karunakaran, Kirill Alexandrov, Melanie R. Shakespear, Mark A. Schembri, David P. Fairlie, and Matthew J. Sweet
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Multidisciplinary - Abstract
The immune system must be able to respond to a myriad of different threats, each requiring a distinct type of response. Here, we demonstrate that the cytoplasmic lysine deacetylase HDAC7 in macrophages is a metabolic switch that triages danger signals to enable the most appropriate immune response. Lipopolysaccharide (LPS) and soluble signals indicating distal or far-away danger trigger HDAC7-dependent glycolysis and proinflammatory IL-1β production. In contrast, HDAC7 initiates the pentose phosphate pathway (PPP) for NADPH and reactive oxygen species (ROS) production in response to the more proximal threat of nearby bacteria, as exemplified by studies on uropathogenic Escherichia coli (UPEC). HDAC7-mediated PPP engagement via 6-phosphogluconate dehydrogenase (6PGD) generates NADPH for antimicrobial ROS production, as well as D-ribulose-5-phosphate (RL5P) that both synergizes with ROS for UPEC killing and suppresses selective inflammatory responses. This dual functionality of the HDAC7-6PGD-RL5P axis prioritizes responses to proximal threats. Our findings thus reveal that the PPP metabolite RL5P has both antimicrobial and immunomodulatory activities and that engagement of enzymes in catabolic versus anabolic metabolic pathways triages responses to different types of danger for generation of inflammatory versus antimicrobial responses, respectively.
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- 2023
4. The histone deacetylase Hdac7 supports LPS-inducible glycolysis and Il-1β production in murine macrophages via distinct mechanisms
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Matthew J. Sweet, James E. B. Curson, David P. Fairlie, Kaustav Das Gupta, Robert Reid, Ashley Mansell, Denuja Karunakaran, Yizhuo Wang, Rishika Abrol, Divya Ramnath, Antje Blumenthal, and Junxian Lim
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Lipopolysaccharides ,Male ,Interleukin-1beta ,Immunology ,Inflammation ,Biology ,Histone Deacetylases ,Histones ,Mice ,medicine ,Animals ,Humans ,Immunology and Allergy ,Macrophage ,Mice, Knockout ,Macrophages ,HDAC7 ,Acetylation ,Cell Biology ,Macrophage Activation ,HDAC4 ,Cell biology ,Mice, Inbred C57BL ,Citric acid cycle ,TLR4 ,Histone deacetylase ,medicine.symptom ,Glycolysis - Abstract
TLRs reprogram macrophage metabolism, enhancing glycolysis and promoting flux through the tricarboxylic acid cycle to enable histone acetylation and inflammatory gene expression. The histone deacetylase (HDAC) family of lysine deacetylases regulates both TLR-inducible glycolysis and inflammatory responses. Here, we show that the TLR4 agonist LPS, as well as agonists of other TLRs, rapidly increase enzymatic activity of the class IIa HDAC family (HDAC4, 5, 7, 9) in both primary human and murine macrophages. This response was abrogated in murine macrophages deficient in histone deacetylase 7 (Hdac7), highlighting a selective role for this specific lysine deacetylase during immediate macrophage activation. With the exception of the TLR3 agonist polyI:C, TLR-inducible activation of Hdac7 enzymatic activity required the MyD88 adaptor protein. The rapid glycolysis response, as assessed by extracellular acidification rate, was attenuated in Hdac7-deficient mouse macrophages responding to submaximal LPS concentrations. Surprisingly however, reconstitution of these cells with either wild-type or an enzyme-dead mutant of Hdac7 enhanced LPS-inducible glycolysis, whereas only the former promoted production of the inflammatory mediators Il-1β and Ccl2. Thus, Hdac7 enzymatic activity is required for TLR-inducible production of specific inflammatory mediators, whereas it acts in an enzyme-independent fashion to reprogram metabolism in macrophages responding to submaximal LPS concentrations. Hdac7 is thus a bifurcation point for regulated metabolism and inflammatory responses in macrophages. Taken together with existing literature, our findings support a model in which submaximal and maximal activation of macrophages via TLR4 instruct glycolysis through distinct mechanisms, leading to divergent biological responses.
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- 2021
5. Histone deacetylase 7: a signalling hub controlling development, inflammation, metabolism and disease
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Yizhuo Wang, Rishika Abrol, Jeffrey Y. W. Mak, Kaustav Das Gupta, Divya Ramnath, Denuja Karunakaran, David P. Fairlie, and Matthew J. Sweet
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Cell Biology ,Molecular Biology ,Biochemistry - Abstract
Histone deacetylases (HDACs) catalyse removal of acetyl groups from lysine residues on both histone and non-histone proteins to control numerous cellular processes. Of the 11 zinc-dependent classical HDACs, HDAC4, 5, 7 and 9 are class IIa HDAC enzymes that regulate cellular and developmental processes through both enzymatic and non-enzymatic mechanisms. Over the last two decades, HDAC7 has been associated with key roles in numerous physiological and pathological processes. Molecular, cellular, in vivo and disease association studies have revealed that HDAC7 acts through multiple mechanisms to control biological processes in immune cells, osteoclasts, muscle, the endothelium and epithelium. This HDAC protein regulates gene expression, cell proliferation, cell differentiation and cell survival and consequently controls development, angiogenesis, immune functions, inflammation and metabolism. This review focuses on the cell biology of HDAC7, including the regulation of its cellular localisation and molecular mechanisms of action, as well as its associative and causal links with cancer and inflammatory, metabolic and fibrotic diseases. We also review the development status of small molecule inhibitors targeting HDAC7 and their potential for intervention in different disease contexts.
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- 2022
6. SCIMP is a spatiotemporal transmembrane scaffold for Erk1/2 to direct pro-inflammatory signaling in TLR-activated macrophages
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Matthew J. Sweet, Richard Lucas, Lin Luo, James E. B. Curson, Kaustav Das Gupta, Yvette W. H. Koh, Nicholas D. Condon, Neeraj Tuladhar, Kate Schroder, Jennifer L. Stow, Liping Liu, Sabrina Sofia Burgener, and Evan Ingley
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MAP Kinase Signaling System ,medicine.medical_treatment ,Mice, Transgenic ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Animals ,Macrophage ,Phosphorylation ,030304 developmental biology ,0303 health sciences ,Toll-like receptor ,Mitogen-Activated Protein Kinase 3 ,Innate immune system ,Chemistry ,Kinase ,Macrophages ,Toll-Like Receptors ,Transmembrane protein ,Cell biology ,Toll-Like Receptor 4 ,Cytokine ,030220 oncology & carcinogenesis ,TLR4 ,Cytokines ,medicine.symptom ,Signal Transduction - Abstract
Immune cells are armed with Toll-like receptors (TLRs) for sensing and responding to pathogens and other danger cues. The role of extracellular-signal-regulated kinases 1/2 (Erk1/2) in TLR signaling remains enigmatic, with both pro- and anti-inflammatory functions described. We reveal here that the immune-specific transmembrane adaptor SCIMP is a direct scaffold for Erk1/2 in TLR pathways, with high-resolution, live-cell imaging revealing that SCIMP guides the spatial and temporal recruitment of Erk2 to membrane ruffles and macropinosomes for pro-inflammatory TLR4 signaling. SCIMP-deficient mice display defects in Erk1/2 recruitment to TLR4, c-Fos activation, and pro-inflammatory cytokine production, with these effects being phenocopied by Erk1/2 signaling inhibition. Our findings thus delineate a selective role for SCIMP as a key scaffold for the membrane recruitment of Erk1/2 kinase to initiate TLR-mediated pro-inflammatory responses in macrophages.
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- 2021
7. Nicotinamide riboside attenuates age-associated metabolic and functional changes in hematopoietic stem cells
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Quan Nguyen, Brenda Williams, Matthew J. Sweet, Xiaoli Chen, Nikita Deshpande, Kaustav Das Gupta, Jose M. Polo, Ronan Kapetanovic, Madeline Fulton, Christian M. Nefzger, Jinhua Li, Susan K. Nilsson, Shen Y. Heazlewood, Robert G. Parton, Jan Schröder, Felix Kraus, Benjamin Cao, Jessica Hatwell-Humble, James Rae, Tony Pham, Chad K. Heazlewood, Hamed Yari, Yu Bo Yang Sun, Michael T. Ryan, Xuan Sun, and Marina Naval-Sanchez
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0301 basic medicine ,Niacinamide ,Aging ,Science ,General Physics and Astronomy ,Bone Marrow Cells ,Mice, Transgenic ,Pyridinium Compounds ,Mitochondrion ,Biology ,Models, Biological ,General Biochemistry, Genetics and Molecular Biology ,Oxidative Phosphorylation ,Transcriptome ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,medicine ,Animals ,Cells, Cultured ,Multidisciplinary ,Gene Expression Profiling ,Age Factors ,General Chemistry ,Hematopoietic Stem Cells ,NAD ,Cell biology ,Mitochondria ,Transplantation ,Mice, Inbred C57BL ,Haematopoiesis ,030104 developmental biology ,medicine.anatomical_structure ,chemistry ,Gene Expression Regulation ,Ageing ,Nicotinamide riboside ,Bone marrow ,Stem cell ,030217 neurology & neurosurgery - Abstract
With age, hematopoietic stem cells (HSC) undergo changes in function, including reduced regenerative potential and loss of quiescence, which is accompanied by a significant expansion of the stem cell pool that can lead to haematological disorders. Elevated metabolic activity has been implicated in driving the HSC ageing phenotype. Here we show that nicotinamide riboside (NR), a form of vitamin B3, restores youthful metabolic capacity by modifying mitochondrial function in multiple ways including reduced expression of nuclear encoded metabolic pathway genes, damping of mitochondrial stress and a decrease in mitochondrial mass and network-size. Metabolic restoration is dependent on continuous NR supplementation and accompanied by a shift of the aged transcriptome towards the young HSC state, more youthful bone marrow cellular composition and an improved regenerative capacity in a transplant setting. Consequently, NR administration could support healthy ageing by re-establishing a more youthful hematopoietic system.
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- 2019
8. Class IIa Histone Deacetylases Drive Toll-like Receptor-Inducible Glycolysis and Macrophage Inflammatory Responses via Pyruvate Kinase M2
- Author
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Mark P. Hodson, Brett M. Collins, Weijun Xu, Alexander J. Stevenson, Alun Jones, Gregory M. Kelly, Antje Blumenthal, Wayne A. Johnston, Robert Reid, Shayli Varasteh Moradi, James E. B. Curson, Kathryn A. Tunny, Divya Ramnath, Melanie R. Shakespear, Kirill Alexandrov, Matthew J. Sweet, Jessica B. von Pein, Lin Luo, Ambika M. V. Murthy, Kaustav Das Gupta, David P. Fairlie, Daniel M. Hohenhaus, Abishek Iyer, Jennifer L. Stow, Vikas A. Tillu, Jennifer H. Gunter, and Takumi Kobayashi
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0301 basic medicine ,Lipopolysaccharides ,Pyruvate Kinase ,Inflammation ,PKM2 ,General Biochemistry, Genetics and Molecular Biology ,Histone Deacetylases ,Proinflammatory cytokine ,03 medical and health sciences ,Mice ,0302 clinical medicine ,medicine ,Animals ,Humans ,Glycolysis ,lcsh:QH301-705.5 ,Toll-like receptor ,Chemistry ,Macrophages ,Toll-Like Receptors ,HDAC7 ,Acetylation ,Hypoxia-Inducible Factor 1, alpha Subunit ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,HEK293 Cells ,RAW 264.7 Cells ,lcsh:Biology (General) ,Anaerobic glycolysis ,medicine.symptom ,030217 neurology & neurosurgery ,Pyruvate kinase ,Protein Binding - Abstract
Summary: Histone deacetylases (HDACs) drive innate immune cell-mediated inflammation. Here we identify class IIa HDACs as key molecular links between Toll-like receptor (TLR)-inducible aerobic glycolysis and macrophage inflammatory responses. A proteomic screen identified the glycolytic enzyme pyruvate kinase M isoform 2 (Pkm2) as a partner of proinflammatory Hdac7 in murine macrophages. Myeloid-specific Hdac7 overexpression in transgenic mice amplifies lipopolysaccharide (LPS)-inducible lactate and promotes a glycolysis-associated inflammatory signature. Conversely, pharmacological or genetic targeting of Hdac7 and other class IIa HDACs attenuates LPS-inducible glycolysis and accompanying inflammatory responses in macrophages. We show that an Hdac7-Pkm2 complex acts as an immunometabolism signaling hub, whereby Pkm2 deacetylation at lysine 433 licenses its proinflammatory functions. Disrupting this complex suppresses inflammatory responses in vitro and in vivo. Class IIa HDACs are thus pivotal intermediates connecting TLR-inducible glycolysis to inflammation via Pkm2. : Das Gupta et al. show that HDAC7 and other class IIa HDAC enzymes control macrophage metabolism. They initiate TLR-inducible glycolysis in these cells and interact with the glycolytic enzyme PKM2 to drive inflammatory responses in vitro and in vivo. Class IIa HDAC inhibitors may have potential for attenuating immunometabolism-linked inflammation. Keywords: glycolysis, histone deacetylases, immunometabolism, inflammation, lysine acetylation, macrophage, post-translational modification, pyruvate kinase, toll-like receptor
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- 2018
9. Histone Deacetylase Inhibitors Promote Mitochondrial Reactive Oxygen Species Production and Bacterial Clearance by Human Macrophages
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David P. Fairlie, Matthew J. Sweet, Robert Reid, Ronan Kapetanovic, Kaustav Das Gupta, Abishek Iyer, and Juliana K. Ariffin
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Salmonella typhimurium ,0301 basic medicine ,Indoles ,Pyridines ,Phagocytosis ,Antineoplastic Agents ,Mitochondrion ,Biology ,Histone Deacetylase 6 ,Hydroxamic Acids ,Histone Deacetylases ,Microbiology ,03 medical and health sciences ,Immune system ,Escherichia coli ,Humans ,Macrophage ,Experimental Therapeutics ,Pharmacology (medical) ,Organic Chemicals ,Cells, Cultured ,Pharmacology ,chemistry.chemical_classification ,Reactive oxygen species ,Macrophages ,Intracellular parasite ,HDAC6 ,Bacterial Load ,Mitochondria ,Histone Deacetylase Inhibitors ,030104 developmental biology ,Infectious Diseases ,chemistry ,Benzamides ,Histone deacetylase ,Reactive Oxygen Species - Abstract
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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- 2016
10. Lysine Deacetylases and Regulated Glycolysis in Macrophages
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Abishek Iyer, David P. Fairlie, Melanie R. Shakespear, Amit Singhal, Kaustav Das Gupta, Matthew J. Sweet, and Catherine Y. Cheng
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0301 basic medicine ,Protein family ,Immunology ,Lysine ,Histone Deacetylases ,Histones ,03 medical and health sciences ,Immunology and Allergy ,Macrophage ,Animals ,Humans ,Sirtuins ,Glycolysis ,Gene ,biology ,Chemistry ,Macrophages ,Acetylation ,Cell biology ,Citric acid cycle ,030104 developmental biology ,Histone ,biology.protein - Abstract
Regulated cellular metabolism has emerged as a fundamental process controlling macrophage functions, but there is still much to uncover about the precise signaling mechanisms involved. Lysine acetylation regulates the activity, stability, and/or localization of metabolic enzymes, as well as inflammatory responses, in macrophages. Two protein families, the classical zinc-dependent histone deacetylases (HDACs) and the NAD-dependent HDACs (sirtuins, SIRTs), mediate lysine deacetylation. We describe here mechanisms by which classical HDACs and SIRTs directly regulate specific glycolytic enzymes, as well as evidence that links these protein deacetylases to the regulation of glycolysis-related genes. In these contexts, we discuss HDACs and SIRTs as key control points for regulating immunometabolism and inflammatory outputs from macrophages.
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- 2017
11. Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases
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Matthew J. Sweet, Abishek Iyer, Kaustav Das Gupta, Melanie R. Shakespear, and David P. Fairlie
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0301 basic medicine ,chemistry.chemical_classification ,biology ,Immunology ,Inflammation ,Review ,Phenotype ,3. Good health ,03 medical and health sciences ,030104 developmental biology ,0302 clinical medicine ,Histone ,Immune system ,Enzyme ,chemistry ,biology.protein ,medicine ,Immunology and Allergy ,Macrophage ,Histone deacetylase ,medicine.symptom ,030217 neurology & neurosurgery ,General Nursing ,Function (biology) - Abstract
Macrophages have central roles in danger detection, inflammation and host defense, and consequently, these cells are intimately linked to most disease processes. Major advances in our understanding of the development and function of macrophages have recently come to light. For example, it is now clear that tissue-resident macrophages can be derived from either blood monocytes or through local proliferation of phagocytes that are originally seeded during embryonic development. Metabolic state has also emerged as a major control point for macrophage activation phenotypes. Herein, we review recent literature linking the histone deacetylase (HDAC) family of enzymes to macrophage development and activation, particularly in relation to these recent developments. There has been considerable interest in potential therapeutic applications for small molecule inhibitors of HDACs (HDACi), not only for cancer, but also for inflammatory and infectious diseases. However, the enormous range of molecular and cellular processes that are controlled by different HDAC enzymes presents a potential stumbling block to clinical development. We therefore present examples of how classical HDACs control macrophage functions, roles of specific HDACs in these processes and approaches for selective targeting of drugs, such as HDACi, to macrophages. Development of selective inhibitors of macrophage-expressed HDACs and/or selective delivery of pan HDACi to macrophages may provide avenues for enhancing efficacy of HDACi in therapeutic applications, while limiting unwanted side effects.
- Published
- 2016
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