Epigenetics in sepsis: targeting histone deacetylases

https://doi.org/10.1016/j.ijantimicag.2013.04.004Get rights and content

Abstract

Severe sepsis and septic shock are lethal complications of infection, characterised by dysregulated inflammatory and immune responses. Our understanding of the pathogenesis of sepsis has improved markedly in recent years, but unfortunately has not been translated into efficient treatment strategies. Epigenetic mechanisms such as covalent modification of histones by acetylation are master regulators of gene expression under physiological and pathological conditions, and strongly impact on inflammatory and host defence responses. Histone acetylation is controlled by histone acetyltransferases and histone deacetylases (HDACs), which affect gene expression also by targeting non-histone transcriptional regulators. Numerous HDAC inhibitors (HDACi) are being tested in clinical trials, primarily for the treatment of cancer. We performed the first comprehensive study of the impact of HDACi on innate immune responses in vitro and in vivo. We showed that HDACi act essentially as negative regulators of the expression of critical immune receptors and antimicrobial pathways in innate immune cells. In agreement, HDACi impaired phagocytosis and killing of bacteria by macrophages, and increased susceptibility to non-severe bacterial and fungal infections. Strikingly, proof-of-principle studies demonstrated that HDACi protect from lethal toxic shock and septic shock. Overall, our observations argue for a close monitoring of the immunological and infection status of patients treated with HDACi, especially immunocompromised cancer patients. They also support the concept of pharmacological inhibitors of HDACs as promising drugs to treat inflammatory diseases, including sepsis.

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

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