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Epigenetics in sepsis: targeting histone deacetylases.
Journal article

Epigenetics in sepsis: targeting histone deacetylases.

  • Ciarlo E Infectious Diseases Service, Department of Medicine, Centre hospitalier universitaire vaudois and University of Lausanne, rue du Bugnon 46, Lausanne, Switzerland.
  • Savva A
  • Roger T
  • 2013-05-14
Published in:
  • International journal of antimicrobial agents. - 2013
Animals
Bacteria
Disease Models, Animal
Enzyme Inhibitors
Epigenesis, Genetic
Histone Deacetylases
Immunity, Innate
Macrophages
Sepsis
Shock, Septic
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://folia.unifr.ch/global/documents/122889
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