Platelets accelerate lipid peroxidation and induce pathogenic neutrophil extracellular trap release.

Neutrophil extracellular traps (NETs), an important host defense mechanism, are assembled after the release of decondensed chromatin and other nuclear components by a process termed NETosis. However, excessive NET release destroys surrounding tissues, leading to conditions such as sepsis where platelets are implicated in the pathogenic switch of NETosis. Here, we show that platelets trigger iron accumulation and promote lipid peroxide production in neutrophils co-stimulated with lipopolysaccharide and platelets in vitro, resulting in the induction of NETosis. We also screened for compounds that inhibit lipid peroxidation, identified 8-methyl-N-geranyl-6-nonamide (capsaicin), and assessed its potential in suppressing platelet-mediated pathogenic NETosis. Capsaicin inhibited lipopolysaccharide/platelet-induced cellular lipid peroxidation and suppressed NETosis in vitro. Furthermore, capsaicin attenuated NETosis in a mouse model of lipopolysaccharide-induced lung inflammation. Our findings provide an original therapeutic strategy to target lipid peroxidation and pave the way for drug development for a wide range of NETosis-related diseases.