Epigenetics in sepsis: targeting histone deacetylases.

Area of Science:

• Immunology
• Molecular Biology
• Pharmacology

Background:

• Severe sepsis and septic shock are life-threatening conditions resulting from dysregulated immune responses to infection.
• Epigenetic modifications, like histone acetylation, significantly influence inflammatory and host defense pathways.
• Histone deacetylases (HDACs) regulate gene expression and are targets for cancer therapies.

Purpose of the Study:

• To investigate the comprehensive impact of histone deacetylase inhibitors (HDACi) on innate immune responses.
• To evaluate the potential of HDACi as therapeutic agents for sepsis and related inflammatory conditions.

Main Methods:

• In vitro and in vivo studies assessing the effects of HDACi on innate immune cells.
• Analysis of immune receptor expression and antimicrobial pathway activity.
• Assessment of macrophage phagocytosis and bacterial killing capacity.
• Evaluation of infection susceptibility and protection against lethal septic shock models.

Main Results:

• HDACi function as negative regulators of critical immune receptors and antimicrobial pathways in innate immune cells.
• HDACi treatment impaired macrophage phagocytosis and bacterial clearance, increasing susceptibility to infections.
• HDACi demonstrated significant protection against lethal toxic shock and septic shock in proof-of-principle studies.

Conclusions:

• HDACi modulate innate immunity, with potential dual effects on infection susceptibility and sepsis treatment.
• Close monitoring of immune and infection status is crucial for patients receiving HDACi, particularly immunocompromised individuals.
• Pharmacological inhibition of HDACs holds promise for treating inflammatory diseases, including sepsis.