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

Abstract

Anti-β2-glycoprotein I (anti-β2GPI) is an anti-phospholipid antibody that specifically binds to β2GPI. 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-β2GPI 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-β2GPI/β2GPI is able to induce neutrophil pyroptosis, thereby driving these cells to release IL-1β 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-β2GPI/β2GPI-induced neutrophil pyroptosis. These pyroptotic neutrophils were also observed to release large amounts of high mobility group box protein 1, which, together with IL-1β, 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-β2GPI anti- body-associated CI.