Neutrophil extracellular traps promote macrophage pyroptosis in sepsis

Area of Science:

• Immunology
• Cellular Biology
• Infectious Disease

Background:

• Polymorphonuclear neutrophils (PMNs) combat infection via phagocytosis, degranulation, and neutrophil extracellular traps (NETs).
• NETs are chromatin structures with antimicrobial components that trap and kill extracellular pathogens.
• Regulated cell death pathways, like pyroptosis, play critical roles in inflammation and host defense.

Purpose of the Study:

• To identify a novel mechanism by which NETs influence macrophage (Mϕ) behavior during infection.
• To investigate the role of NETs in inducing Mϕ pyroptosis in a mouse sepsis model.
• To elucidate the molecular signaling cascade linking NETs to Mϕ pyroptosis and subsequent inflammation.

Main Methods:

• Utilized a mouse sepsis model to study the interaction between neutrophils and macrophages.
• Investigated the role of NET-derived HMGB1 and its signaling pathways (RAGE, dynamin) in Mϕ activation.
• Analyzed intracellular events including lysosomal rupture, cathepsin B release, pyroptosome formation, and caspase-1 activation.

Main Results:

• NETs were found to induce macrophage pyroptosis, a caspase-1-dependent cell death.
• NET-derived HMGB1 activates RAGE and dynamin-dependent signaling, initiating an intracellular cascade in Mϕ.
• This cascade involves cathepsin B release, pyroptosome formation, and caspase-1 activation, leading to Mϕ pyroptosis.
• Macrophage pyroptosis was shown to augment inflammatory responses in the context of sepsis.

Conclusions:

• NETs play a pro-inflammatory role by inducing macrophage pyroptosis.
• The NET-macrophage interaction, mediated by HMGB1 signaling, significantly influences sepsis progression.
• Findings reveal a novel mechanism contributing to inflammation following infection, involving PMN-Mϕ crosstalk.