Epigenetics in sepsis: targeting histone deacetylases

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