Epigenetics in sepsis: targeting histone deacetylases
Section snippets
Innate immunity
Host integrity is preserved by the innate immune system, which provides the first line of defence against microbial infections. Sensing of pathogens by innate immune cells is mediated by pattern recognition receptors (PRRs) or molecules specialised in the recognition of conserved structures of micro-organisms. Families of PRRs include the Toll-like receptors (TLRs), NOD-like receptors (NLRs), C-type lectin receptors (CLRs), RIG-I-like receptors (RLRs) and AIM2-like receptors (ALRs). Recognition
Sepsis
Innate immune responses have to be tightly regulated, and failure to mount an appropriate defence response to microbial invasion may have dramatic consequences for the host. Severe sepsis and septic shock are life-threatening complications of infection. Despite recent advances in antimicrobial therapy and supportive care, the prognosis of patients with severe infections remains grim, with mortality rates ranging from 20% to 80%. Severe sepsis and septic shock may be caused by highly virulent
The inflammatory response in sepsis
Our understanding of the pathogenesis of sepsis has progressed considerably over previous decades. The earlier view of sepsis resulting merely from an exuberant inflammatory response has been recently reconsidered. The postulate of an initial overwhelming inflammatory response [the systemic inflammatory response syndrome (SIRS)] followed by a state of immunosuppression [the compensatory anti-inflammatory response syndrome (CARS)] does not reflect the complexity of events occurring in severely
Epigenetic control of gene expression
The term epigenetics was introduced to characterise heritable mechanisms affecting gene expression without affecting the DNA sequence itself. This definition has been extended in past years to those changes not entirely heritable but functionally linked to the genome [8]. Epigenetic information includes DNA methylation, non-coding RNAs and post-translational modification of histone proteins. In the following sections, we will focus on histone modifications by acetylation as an important
Histone deacetylases
HDACs were named according to their first identified substrates, i.e. histones. As the list of non-histone targets of HDACs is constantly increasing [12], some have proposed to rename HDACs as lysine deacetylases (KDACs). The 18 mammalian HDACs are classified in classes I–IV based on their homology with yeast HDACs, subcellular localisation and enzymatic activity. Classes I, II and IV comprise the ‘classical’ Zn2+-dependent HDAC1–11, whilst class III encompasses the NAD+-dependent sirtuins
Histone deacetylase inhibitors and their impact on inflammatory diseases
In the late 1970s, butyrate, a short fatty acid, was reported to have anti-cancer activities and to suppress histone deacetylation. Ten years later, trichostatin A (TSA) was identified as the first specific HDACi. These pioneer studies stimulated the development of new HDACi as anti-cancer drugs. Research in the field has been very successful. Suberoylanilide hydroxamic acid (SAHA) (vorinostat, Zolinza™) and romidepsin (FK228, Istodax®, also known as depsipeptide FR901228) have recently been
Histone deacetylase inhibitors impair host defences: the bad and the good sides
Following the initial description of the anti-inflammatory activity of HDACi, several studies reported that HDACi impact on innate immune responses at many levels. HDACi inhibit cytokine and nitric oxide (NO) release and co-stimulatory molecule expression by PBMCs, monocytes, macrophages and DCs stimulated with microbial products and pro-inflammatory cytokines (Table 1). Moreover, HDACi block the production of Th1- and Th17-polarising cytokines, which drive the Th1 and Th17 protective responses
Perspectives
HDACi represent a class of promising drugs not only in the field of cancer but also in the field of immune diseases. HDACi may offer advantages compared with cytokine blocking agents, including transient inhibition of cytokine production and inducing ‘global’ gene remodelling. HDACi may also offer a certain level of selectivity, as different HDACi influence specific signalling cascades. This advantage will be improved with the synthesis of HDAC-isotype-specific inhibitors. Interestingly, the
Acknowledgments
The authors would like to thank all our collaborators that participated in our studies, and apologise to the numerous authors whose work was not referenced owing to space limitations.
Funding: TR received grants from the Swiss National Science Foundation (310000_114073 and 310030_132744) and an MSD award from the Swiss Society for Infectious Diseases. AS is the recipient of a grant from the Porphyrogenis Foundation. EC declares no competing interests.
Competing interests: None declared.
Ethical
References (41)
- et al.
Toll-like receptors and their crosstalk with other innate receptors in infection and immunity
Immunity
(2011) - et al.
Host–pathogen interactions in sepsis
Lancet Infect Dis
(2008) Chromatin modifications and their function
Cell
(2007)- et al.
Acetylation and deacetylation of non-histone proteins
Gene
(2005) - et al.
Inhibition of HDAC9 increases T regulatory cell function and prevents colitis in mice
Gastroenterology
(2010) - et al.
Human CD25highFoxp3pos regulatory T cells differentiate into IL-17-producing cells
Blood
(2008) - et al.
A therapeutic strategy uses histone deacetylase inhibitors to modulate the expression of genes involved in the pathogenesis of rheumatoid arthritis
Mol Ther
(2003) - et al.
Transcriptional therapy with the histone deacetylase inhibitor trichostatin A ameliorates experimental autoimmune encephalomyelitis
J Neuroimmunol
(2005) - et al.
Reduction of graft-versus-host disease by histone deacetylase inhibitor suberonylanilide hydroxamic acid is associated with modulation of inflammatory cytokine milieu and involves inhibition of STAT1
Exp Hematol
(2006) - et al.
Histone deacetylase inhibitors impair innate immune responses to Toll-like receptor agonists and to infection
Blood
(2011)
Histone deacetylase activities are required for innate immune cell control of Th1 but not Th2 effector cell function
Blood
Histone deacetylase inhibitors repress macrophage migration inhibitory factor (MIF) expression by targeting MIF gene transcription through a local chromatin deacetylation
Biochim Biophys Acta
Inflammasomes and their roles in health and disease
Annu Rev Cell Dev Biol
Sepsis: something old, something new, and a systems view
J Crit Care
Harmful molecular mechanisms in sepsis
Nat Rev Immunol
Human genetic susceptibility to infectious disease
Nat Rev Genet
Genetic variation in Toll-like receptors and disease susceptibility
Nat Immunol
Chromatin replication and epigenome maintenance
Nat Rev Mol Cell Biol
Molecular mechanisms and potential functions of histone demethylases
Nat Rev Mol Cell Biol
Histone methylation: a dynamic mark in health, disease and inheritance
Nat Rev Genet
Cited by (58)
Valproic acid attenuates sepsis-induced myocardial dysfunction in rats by accelerating autophagy through the PTEN/AKT/mTOR pathway
2019, Life SciencesCitation Excerpt :Histone acetylation modification is an important mechanism of epigenetic regulation. Previous studies have shown that histone deacetylase (HDAC) inhibitor plays a protective role in sepsis, but the underlying mechanisms remain unclear [17–21]. Prior research has also found that valproic acid (VPA), a class I HDAC inhibitor, can induce autophagy [22].