Rosa María TorderaMaría Cortés-EriceChapter

First Online: 12 May 2021

Part of the Reviews of Physiology, Biochemistry and Pharmacology book series (REVIEWS, volume 180)Abstract

Histone deacetylases (HDACs) are a family of 18 members that participate in the epigenetic regulation of gene expression. In addition to histones, some HDACs also deacetylate transcription factors and specific cytoplasmic proteins.

Monocytes, as part of the innate immune system, maintain tissue homeostasis and help fight infections and cancer. In these cells, HDACs are involved in multiple processes including proliferation, migration, differentiation, inflammatory response, infections, and tumorigenesis. Here, a systematic description of the role that most HDACs play in these functions is reviewed. Specifically, some HDACs induce a pro-inflammatory response and play major roles in host defense. Conversely, other HDACs reprogram monocytes and macrophages towards an immunosuppressive phenotype. The right balance between both types helps monocytes to respond correctly to the different physiological/pathological stimuli. However, aberrant expressions or activities of specific HDACs are associated with autoimmune diseases along with other chronic inflammatory diseases, infections, or cancer.

This paper critically reviews the interesting and extensive knowledge regarding the role of some HDACs in these pathologies. It also shows that as yet, very little progress has been made toward the goal of finding effective HDAC-targeted therapies. However, given their obvious potential, we conclude that it is worth the effort to develop monocyte-specific drugs that selectively target HDAC subtypes with the aim of finding effective treatments for diseases in which our innate immune system is involved.

KeywordsAutoimmune diseases Cancer Epigenetics HDACs inhibitors Immunosuppression Inflammation Macrophage reprogramming Viral infection 

AbbreviationsBMDMs

Bone marrow–derived macrophage cells

COPD

Chronic obstructive pulmonary disease

COX-2

Cyclooxygenase 2

CSE

Cigarette smoke extract

FDA

Food and Drug Administration

FOXO

Forkhead box

HAT

Histone acetyltransferase

HDAC

Histone deacetylase

HIF-1α

Hypoxia-inducible factor 1 alpha

HIV-1

Human immunodeficiency virus 1

HSPCs

Human stem and progenitor cells

IAV

Influenza A virus

IL

Interleukin

JEV

Japanese encephalitis virus

KLF2

Krüppel-like factor 2

LOX-1

Lectin-like oxidized low-density lipoprotein receptor-1

LPMCs

Intestinal lamina propia mononuclear cells

LPS

Lipopolysaccharide

LXR

Liver X receptor

MCP-1

Monocyte chemoattractant protein

MEF2

Myocyte enhancer factor 2

MIP-1α

Macrophage inflammatory protein alpha

MMP9

Matrix metalloproteinase-9

NES

Nuclear export sequence

NF-ĸB

Nuclear factor kappa B

NLS

Nuclear localization sequence

Nrf2

Nuclear factor erythroid 2-related factor 2

PBMCs

Peripheral blood mononuclear cells

PI3Kδ

Phosphoinositide-3-kinase-δ

SAHA

Suberoylanilide hydroxamic acid

SIRT

Sirtuin

TLR

Toll-like receptor

TNFα

Tumoral necrosis factor alpha

This is a preview of subscription content,

log in

to check access.

NotesAcknowledgements

We would like to thank the Departamento de Salud (Gobierno de Navarra, Spain) for funding a project focused on the role of different HDACs on peripheral monocytes in depressed patients. Thanks to Ministerio de Ciencia, Innovación y Universidades (Gobierno de España) for supporting to M.C.E (FPU17/05039) with a fellowship. In addition, thanks to all the patients and volunteers that are collaborating in our research, and specially, to Ms Sandra Lizaso for all her technical support in all the monocyte studies. The authors declare no competing interests. Thanks to O.L.F for inspiring me the initial idea of this review during the first weeks of the Covid-19 pandemic.

References

Adenuga D, Yao H, March TH et al (2009) Histone deacetylase 2 is phosphorylated, ubiquitinated, and degraded by cigarette smoke. Am J Respir Cell Mol Biol 40:464–473.

 https://doi.org/10.1165/rcmb.2008-0255OCCrossRefPubMedGoogle Scholar

Adhya D, Dutta K, Kundu K, Basu A (2013) Histone deacetylase inhibition by Japanese encephalitis virus in monocyte/macrophages: a novel viral immune evasion strategy. Immunobiology 218:1235–1247.

 https://doi.org/10.1016/j.imbio.2013.04.018CrossRefPubMedGoogle Scholar

Algate K, Haynes D, Fitzsimmons T et al (2020) Histone deacetylases 1 and 2 inhibition suppresses cytokine production and osteoclast bone resorption in vitro. J Cell Biochem 121:244–258.

 https://doi.org/10.1002/jcb.29137CrossRefPubMedGoogle Scholar

Angiolilli C, Baeten DL, Radstake TR, Reedquist KA (2017) The acetyl code in rheumatoid arthritis and other rheumatic diseases. Epigenomics 9:447–461

CrossRefGoogle Scholar

Annamanedi M, Kalle AM (2014) Celecoxib sensitizes

Staphylococcus aureus

to antibiotics in macrophages by modulating SIRT1. PLoS One 9:e99285.

 https://doi.org/10.1371/journal.pone.0099285CrossRefPubMedPubMedCentralGoogle Scholar

Aude-Garcia C, Collin-Faure V, Bausinger H et al (2010) Dual roles for MEF2A and MEF2D during human macrophage terminal differentiation and c-Jun expression. Biochem J 430:237–244.

 https://doi.org/10.1042/BJ20100131CrossRefPubMedGoogle Scholar

Barnes PJ (2009) Role of HDAC2 in the pathophysiology of COPD. Annu Rev Physiol 71:451–464

CrossRefGoogle Scholar

Barnes PJ (2010) Theophylline. Pharmaceuticals 3:725–747

CrossRefGoogle Scholar

Barnes PJ (2013) Development of new drugs for COPD. Curr Med Chem 20:1531–1540.

 https://doi.org/10.2174/0929867311320120005CrossRefPubMedGoogle Scholar

Boniakowski AM, den Dekker AD, Davis FM et al (2019) SIRT3 regulates macrophage-mediated inflammation in diabetic wound repair. J Invest Dermatol 139:2528–2537.e2.

 https://doi.org/10.1016/j.jid.2019.05.017CrossRefPubMedPubMedCentralGoogle Scholar

Breitenstein A, Wyss CA, Spescha RD et al (2013) Peripheral blood monocyte Sirt1 expression is reduced in patients with coronary artery disease. PLoS One 8.

 https://doi.org/10.1371/journal.pone.0053106

Cantley MD, Fairlie DP, Bartold PM et al (2011) Inhibitors of histone deacetylases in class I and class II suppress human osteoclasts in vitro. J Cell Physiol 226:3233–3241.

 https://doi.org/10.1002/jcp.22684CrossRefPubMedGoogle Scholar

Cao J, Sun L, Aramsangtienchai P et al (2019) HDAC11 regulates type I interferon signaling through defatty-acylation of SHMT2. Proc Natl Acad Sci U S A 116:5487–5492.

 https://doi.org/10.1073/pnas.1815365116CrossRefPubMedPubMedCentralGoogle Scholar

Carta S, Tassi S, Semino C et al (2006) Histone deacetylase inhibitors prevent exocytosis of interleukin-1β- containing secretory lysosomes: role of microtubules. Blood 108:1618–1626.

 https://doi.org/10.1182/blood-2006-03-014126CrossRefPubMedPubMedCentralGoogle Scholar

Castellucci M, Rossato M, Calzetti F et al (2015) IL-10 disrupts the Brd4-docking sites to inhibit LPS-induced CXCL8 and TNF-α expression in monocytes: implications for chronic obstructive pulmonary disease. J Allergy Clin Immunol 136:781–791.e9.

 https://doi.org/10.1016/j.jaci.2015.04.023CrossRefPubMedGoogle Scholar

Chan SH, Hung CH, Shih JY et al (2017) SIRT1 inhibition causes oxidative stress and inflammation in patients with coronary artery disease. Redox Biol 13:301–309.

 https://doi.org/10.1016/j.redox.2017.05.027CrossRefPubMedPubMedCentralGoogle Scholar

Chang HH, Wang W, Bong SJ et al (2008a) Protein kinase D-dependent phosphorylation and nuclear export of histone deacetylase 5 mediates vascular endothelial growth factor-induced gene expression and angiogenesis. J Biol Chem 283:14590–14599.

 https://doi.org/10.1074/jbc.M800264200CrossRefGoogle Scholar

Chang YH, Lin IL, Tsay GJ et al (2008b) Elevated circulatory MMP-2 and MMP-9 levels and activities in patients with rheumatoid arthritis and systemic lupus erythematosus. Clin Biochem 41:955–959.

 https://doi.org/10.1016/j.clinbiochem.2008.04.012CrossRefPubMedGoogle Scholar

Charron CE, Chou PC, Coutts DJC et al (2009) Hypoxia-inducible factor 1α induces corticosteroid-insensitive inflammation via reduction of histone deacetylase-2 transcription. J Biol Chem 284:36047–36054.

 https://doi.org/10.1074/jbc.M109.025387CrossRefPubMedPubMedCentralGoogle Scholar

Chen LF, Greene WC (2004) Shaping the nuclear action of NF-κB. Nat Rev Mol Cell Biol 5:392–401

CrossRefGoogle Scholar

Choo QY, Ho PC, Tanaka Y, Lin HS (2013) The histone deacetylase inhibitors MS-275 and SAHA suppress the p38 mitogen-activated protein kinase signaling pathway and chemotaxis in rheumatoid arthritic synovial fibroblastic E11 cells. Molecules 18:14085–14095.

 https://doi.org/10.3390/molecules181114085CrossRefPubMedPubMedCentralGoogle Scholar

Collins T, Cybulsky MI (2001) NF-κB: pivotal mediator or innocent bystander in atherogenesis? J Clin Invest 107:255–264

CrossRefGoogle Scholar

Cosio BG, Tsaprouni L, Ito K et al (2004) Theophylline restores histone deacetylase activity and steroid responses in COPD macrophages. J Exp Med 200:689–695.

 https://doi.org/10.1084/jem.20040416CrossRefPubMedPubMedCentralGoogle Scholar

Cosío BG, Jahn A, Iglesias A et al (2015) Haemophilus influenzae induces steroid-resistant inflammatory responses in COPD. BMC Pulm Med 15:157.

 https://doi.org/10.1186/s12890-015-0155-3CrossRefPubMedPubMedCentralGoogle Scholar

Crane MJ, Hokeness-Antonelli KL, Salazar-Mather TP (2009) Regulation of inflammatory monocyte/macrophage recruitment from the bone marrow during murine cytomegalovirus infection: role for type I interferons in localized induction of CCR2 ligands. J Immunol 183:2810–2817.

 https://doi.org/10.4049/jimmunol.0900205CrossRefPubMedGoogle Scholar

Crosbie PAJ, Woodhead MA (2009) Long-term macrolide therapy in chronic inflammatory airway diseases. Eur Respir J 33:171–181

CrossRefGoogle Scholar

Crujeiras AB, Parra D, Goyenechea E, Martínez JA (2008) Sirtuin gene expression in human mononuclear cells is modulated by caloric restriction. Eur J Clin Investig 38:672–678.

 https://doi.org/10.1111/j.1365-2362.2008.01998.xCrossRefGoogle Scholar

Dai Y, Rahmani M, Dent P, Grant S (2005) Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-κB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 25:5429–5444.

 https://doi.org/10.1128/mcb.25.13.5429-5444.2005CrossRefPubMedPubMedCentralGoogle Scholar

Dali-Youcef N, Lagouge M, Froelich S et al (2007) Sirtuins: the “magnificent seven”, function, metabolism and longevity. Ann Med 39:335–345

CrossRefGoogle Scholar

Das Gupta K, Shakespear MR, Iyer A et al (2016) Histone deacetylases in monocyte/macrophage development, activation and metabolism: refining HDAC targets for inflammatory and infectious diseases. Clin Trans Immunol 5:e62

CrossRefGoogle Scholar

Daskalaki MG, Tsatsanis C, Kampranis SC (2018) Histone methylation and acetylation in macrophages as a mechanism for regulation of inflammatory responses. J Cell Physiol 233:6495–6507

CrossRefGoogle Scholar

De Kreutzenberg SV, Ceolotto G, Papparella I et al (2010) Downregulation of the longevity-associated protein sirtuin 1 in insulin resistance and metabolic syndrome: potential biochemical mechanisms. Diabetes 59:1006–1015.

 https://doi.org/10.2337/db09-1187CrossRefPubMedPubMedCentralGoogle Scholar

De Ruijter AJM, Van Gennip AH, Caron HN et al (2003) Histone deacetylases (HDACs): characterization of the classical HDAC family. Biochem J 370:737–749

CrossRefGoogle Scholar

Dutot M, Fagon R, Hemon M, Rat P (2012) Antioxidant, anti-inflammatory, and anti-senescence activities of a phlorotannin-rich natural extract from Brown Seaweed

Ascophyllum nodosum

. Appl Biochem Biotechnol 167:2234–2240.

 https://doi.org/10.1007/s12010-012-9761-1CrossRefPubMedGoogle Scholar

Eccleston A, DeWitt N, Gunter C et al (2007) Epigenetics. Nature 447:395

CrossRefGoogle Scholar

Elmali N, Baysal O, Harma A et al (2007) Effects of resveratrol in inflammatory arthritis. Inflammation 30:1–6.

 https://doi.org/10.1007/s10753-006-9012-0CrossRefPubMedGoogle Scholar

Eskandarian HA, Impens F, Nahori M-A et al (2013) A role for SIRT2-dependent histone H3K18 deacetylation in bacterial infection. Science 341:1238858.

 https://doi.org/10.1126/science.1238858CrossRefPubMed