Anti-β2GPI/β2GPI induces neutrophil pyroptosis and thereby enhances ICAM-1 and IL-8 expression in endothelial cells

Anti-beta(2)-glycoprotein I (anti-beta(2)GPI) is an anti-phospholipid antibody that specifically binds to beta(2)GPI. There is growing evidence that this autoantibody is closely linked to specific thrombotic conditions. Cerebral infarction (CI) is a form of thrombosis associated with high rates of morbidity and mortality. In the present study, it was determined that patients with CI exhibited significantly increased serum anti-beta(2)GPI levels as well as increased NLR family pyrin domain containing 3 (NLRP3) expression within neutrophils, suggesting a potential role for inflammatory cell death in this pathological context. Specifically, it was determined that anti-beta(2)GPI/beta(2)GPI is able to induce neutrophil pyroptosis, thereby driving these cells to release IL-1 beta via a pathway regulated by cell surface Toll-like receptor 4 expression. At the mechanistic level, the double-stranded RNA-dependent protein kinase/p38MAPK/NLRP3 pathway was indicated to govern anti-beta(2)GPI/beta(2)GPI-induced neutrophil pyroptosis. These pyroptotic neutrophils were also observed to release large amounts of high mobility group box protein 1, which, together with IL-1 beta, promoted IL-8 and intercellular cell adhesion molecule-1 upregulation in endothelial cells. In summary, these data suggest that inhibiting neutrophil pyroptosis may represent a viable approach to treating anti-beta(2)GPI anti- body-associated CI.

Automated summary

This study found that patients with cerebral infarction had increased levels of anti-beta(2)GPI antibodies and increased expression of NLRP3 in neutrophils, suggesting a role for inflammatory cell death in this condition. It was determined that anti-beta(2)GPI/beta(2)GPI can induce neutrophil pyroptosis, leading to the release of IL-1 beta. The mechanism involves the double-stranded RNA-dependent protein kinase/p38MAPK/NLRP3 pathway. Pyroptotic neutrophils also release high mobility group box protein 1, which promotes inflammation in endothelial cells.