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.

中文翻译：

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血小板加速脂质过氧化并诱导致病性中性粒细胞胞外陷阱释放


中性粒细胞胞外陷阱 （NET） 是一种重要的宿主防御机制，在释放解聚的染色质和其他核成分后通过称为 NETosis的过程组装。然而，过量的 NET 释放会破坏周围组织，导致脓毒症等情况，其中血小板与 NETosis的致病性转换有关。在这里，我们表明血小板在体外与脂多糖和血小板 共刺激的中性粒细胞中触发铁积累并促进脂质过氧化物的产生，从而导致 NETosis的诱导。我们还筛选了抑制脂质过氧化的化合物，鉴定了 8-甲基-N-香叶酰-6-壬酰胺 （辣椒素），并评估了其在抑制血小板介导的致病性 NETosis.辣椒素在体外抑制脂多糖/血小板诱导的细胞脂质过氧化并抑制 NETosis 。此外，辣椒素减轻了脂多糖诱导的肺部炎症小鼠模型中的 NETosis。我们的研究结果提供了一种针对脂质过氧化的原始治疗策略，并为多种 NETosis 相关疾病的药物开发铺平了道路。