Citrullinated Histone H3 Mediates Sepsis-Induced Lung Injury Through Activating Caspase-1 Dependent Inflammasome...

Area of Science:

• Immunology
• Pathophysiology
• Critical Care Medicine

Background:

• Sepsis causes life-threatening organ dysfunction, often leading to acute lung injury/acute respiratory distress syndrome (ALI/ARDS).
• Neutrophil and macrophage cell death releasing histones contributes to sepsis-induced ALI, but the role of citrullinated histone H3 (CitH3) remains unclear.

Purpose of the Study:

• To investigate the role of citrullinated histone H3 (CitH3) in the pathogenesis of sepsis-induced ALI.
• To determine if CitH3 contributes to inflammation and mortality in sepsis.

Main Methods:

• Measured CitH3 levels in patients with sepsis-induced ARDS.
• Administered CitH3 peptide to mice to induce ALI and tested monoclonal antibody neutralization.
• Investigated CitH3's mechanism of action in bone marrow-derived macrophages and dendritic cells, focusing on Caspase-1 inflammasome activation.

Main Results:

• CitH3 levels were elevated in patients with sepsis-induced ARDS and correlated with oxygenation.
• CitH3 administration induced ALI and Caspase-1 activation in mouse lungs.
• Monoclonal antibody neutralization of CitH3 improved survival and attenuated ALI in a mouse sepsis model.
• CitH3 activates Caspase-1 dependent inflammasome in immune cells, mediating ALI.

Conclusions:

• CitH3 is significantly elevated in sepsis-induced ARDS and contributes to lung injury.
• CitH3 promotes ALI and mortality in sepsis by activating Caspase-1 inflammasome.
• Targeting CitH3 may represent a therapeutic strategy for sepsis-induced ALI.