HDAC2 enhances the antimicrobial activity of neutrophils by promoting the formation of neutrophil extracellular traps (NETs) in sepsis

Introduction: Sepsis is characterized as a life-threatening organ dysfunction resulting from a dysregulated host response to Infection, representing a critical clinical syndrome. Uncontrolled Infection and inflammation are two main characteristics of sepsis. Neutrophil extracellular traps (NETs) is a major mechanism by which neutrophils resist pathogens invasion, but the mechanism of the NETs formation remain completely unclear.

Objectives: This study aims to elucidate the role of Histone Deacetylase 2 (HDAC2) in NETs formation and its impact on antimicrobial and anti-inflammatory activities in sepsis.

Methods: We employed flow cytometry, immunofluorescence and western blotting to assess NETs formation. The effects of HDAC2 on NETs and sepsis outcomes were investigated using an HDAC2 Inhibitor and HDAC2 knockout mice in CLP-induced and LPS-induced sepsis models. Histone modifications in neutrophils were also analyzed to explore HDAC2's regulatory mechanism.

Results: HDAC2 was found to be highly expressed in patients and mice with sepsis. While HDAC2 knockout or inhibition reduced inflammation and improved organ function in non-infectious sepsis, it decreased survival in infectious sepsis. In addition, knockout or inhibition of HDAC2 significantly reduced the NETs formation, and impaired the antimicrobial activities against E. coli Infection in mice. Mechanistically, HDAC2 indirectly promoted H3R17 citrullination to induce the NETs formation through down-regulating H3K18 acetylation and interactively inhibiting CARM1-mediated H3R17 methylation in neutrophils. Furthermore, a dual inhibition strategy targeting HDAC2 and CARM1 not only suppressed inflammation, prevented from multiple organ dysfunction, but also enhanced the antimicrobial activities, which finally improved survival rate of mice with sepsis induced by cecal ligation and puncture (CLP).

Conclusion: Our findings reveal a novel role for HDAC2 in modulating anti-infectious immunity through NETs formation during sepsis. This study provides a potential therapeutic strategy for sepsis by enhancing both antimicrobial and anti-inflammatory responses, offering a promising approach to preserve organ function and improve survival.

Acety-H3K18; Cit-H3R17; HDAC2; Methy-H3R17; Neutrophil extracellular traps; Sepsis.