NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum.
NETosis Is Induced by Complement Component 5a: Implications in the Pathogenesis of Pyoderma Gangrenosum.
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NETosis 由补体成分 5a 诱导：对坏疽性脓皮病发病机制的影响。
DOI：
10.1016/j.jid.2023.06.204
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发表时间：
2024
期刊：
影响因子：
--
通讯作者：
Liu,Yuangang
中科院分区：
文献类型：
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作者：
Wang,Zhiping;Hornick,Noah;Vague,Morgan;Yang,Doris;Keller,Jesse;Kody,Shannon;Leachman,Sancy;Ortega-Loayza,AlexG;Liu,Yuangang
NETosis是通过释放染色质DNA和蛋白酶的宿主抗微生物机制（Brinkmann等人，2004），其导致组织损伤和炎症（Wong等人，2015）。NETosis已经涉及具有无菌炎症的人类疾病的发病机制，包括坏疽性脓毒症（PG）（Croia等人，2021; Eid等人，2021年）。迄今为止，导致PG中NETosis的分子事件在很大程度上是未知的。为了鉴定导致PG中NETosis的因素，我们检索了我们的RNA测序数据库（Ortega-Loayza等人，2022）用于（i）其受体存在于嗜中性粒细胞中的配体和（ii）嗜中性粒细胞中的受体。IL-1β、IL-6、IL-8和补体成分5a受体（C5 aR）（也称为C5 aR 1）被鉴定为PG中NETosis的潜在诱导剂（图1a）。为了鉴定导致PG中NETosis的主要细胞因子，我们比较了由这些细胞因子诱导的中性粒细胞胞外陷阱（NET）形成。在用组分5a（C5 a）处理的中性粒细胞中观察到NET形成，但在用20 nM IL-1β或IL-6处理1小时的那些中未观察到NET形成（图1 B）。IL-8诱导了明显的NET形成，但低于用C5 a观察到的。C5 a的进一步滴定显示NET形成可以由C5 a以剂量依赖性方式诱导（图Ic）。早在C5 a处理后30分钟，C5 a就诱导NET形成（图Id）。这些数据表明，C5 a是在我们的数据库中鉴定的候选物中最有效的NETosis诱导剂。
NETosis is a host antimicrobial mechanism through the release of chromatin DNA and proteases (Brinkmann et al., 2004) that contribute to tissue damage and inflammation (Wong et al., 2015). NETosis has been implicated in the pathogenesis of human diseases with sterile inflammation, including pyoderma gangrenosum (PG)(Croia et al., 2021; Eid et al., 2021). To date, the molecular events contributing to NETosis in PG are largely unknown.To identify the factors that contribute to NETosis in PG, we searched our RNA-sequencing database (Ortega-Loayza et al., 2022) for (i) ligands whose receptors are present in neutrophils and (ii) receptors in neutrophils. IL-1β, IL-6, IL-8, and complement component 5a receptor (C5aR)(also known as C5aR1) were identified as potential inducers of NETosis in PG (Figure 1 a). To identify the main cytokine that contributes to NETosis in PG, we compared neutrophil extracellular trap (NET) formation induced by these cytokines .NET formation was observed in neutrophils treated with component 5a (C5a) but not in those treated with IL-1β or IL-6 at 20 nM for 1 hour (Figure 1 b). IL-8 induced noticeable NET formation but less than that observed with C5a. Further titration of C5a showed that NET formation can be induced by C5a in a dose-dependent manner (Figure 1 c). C5a induced NET formation as early as 30 minutes after C5a treatment (Figure 1 d). These data demonstrate that C5a is the most potent inducer of NETosis among the candidates identified in our database.