The Positive Feedback Interaction Between Mast Cell-Derived Tryptase and NETs Formation in the Pathogenesis of...

Area of Science:

• Neuroscience
• Immunology
• Pathology

Background:

• Sepsis-associated encephalopathy (SAE) causes neuroinflammation and cognitive deficits.
• Neutrophil extracellular traps (NETs) are implicated in neuroinflammation, but their role in SAE and the involvement of mast cells (MCs) are unclear.

Purpose of the Study:

• To investigate the mechanisms of NET formation in SAE.
• To explore the interplay between brain-resident mast cells and neutrophils in SAE pathogenesis.
• To identify potential therapeutic targets for SAE.

Main Methods:

• A cecal ligation and puncture (CLP) model was used to induce SAE in mice.
• Pharmacological agents targeting MCs and their mediators were administered.
• MC-neutrophil co-cultures, advanced imaging, Western blot, and functional assays were employed.

Main Results:

• MC activation significantly enhanced neutrophil infiltration and NET formation in SAE.
• MC-derived tryptase activates the PAR2-MAPK pathway in neutrophils, increasing lactate production.
• Lactate stabilizes PAD4, promoting NETosis and creating a positive feedback loop with MC activation.

Conclusions:

• A novel bidirectional MC-NETs axis drives neuroinflammation in SAE.
• Tryptase-PAR2-MAPK signaling and lactylation-mediated PAD4 stabilization are key mechanisms.
• This pathway presents potential therapeutic targets for SAE intervention.