Interleukin-1β Mediates Arterial Thrombus Formation via NET-Associated Tissue Factor

Area of Science:

• Cardiovascular Biology
• Inflammation Research
• Hematology

Background:

• The CANTOS trial showed Canakinumab (anti-IL-1β antibody) reduced atherothrombotic events in patients with residual inflammatory risk.
• Mechanisms underlying Canakinumab's benefit in preventing atherothrombosis are not fully understood.
• Neutrophil extracellular traps (NETs) and their associated tissue factor (TF) are implicated in arterial thrombosis.

Purpose of the Study:

• To investigate the link between Interleukin-1 beta (IL-1β), NETosis, and TF in atherothrombosis.
• To explore IL-1β as a potential trigger for NETosis and subsequent TF release in ST-elevation myocardial infarction (STEMI) patients.

Main Methods:

• Retrospective analysis of STEMI patients from the SPUM-ACS trial, stratified by C-reactive protein (CRP) levels (high: ≥10 mg/L, low: ≤4 mg/L).
• Measurement of circulating IL-1β, NETosis markers, and NET-associated TF plasma levels.
• Translational research experiments to confirm mechanistic links.

Main Results:

• Patients with high CRP levels exhibited elevated IL-1β, NETosis, and NET-associated TF compared to low CRP patients.
• Similar elevations were observed when patients were stratified by IL-1β levels.
• NETosis and NET-associated TF plasma levels showed a positive correlation.
• IL-1β was identified as the initial trigger for NET-associated TF release.

Conclusions:

• Elevated IL-1β drives NETosis and the release of pro-coagulant TF in STEMI patients.
• This IL-1β-NET-TF pathway provides a potential mechanism for the reduction in atherothrombotic events observed with IL-1β inhibition (Canakinumab) in the CANTOS trial.