Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands;
Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands.
J Immunol. 2018 Aug 15;201(4):1241-1252. doi: 10.4049/jimmunol.1800314. Epub 2018 Jul 9.
Peptidylarginine deiminase 4 (PAD4) catalyzes citrullination of histones, an important step for neutrophil extracellular trap (NET) formation. We aimed to determine the role of PAD4 during pneumonia. Markers of NET formation were measured in lavage fluid from airways of critically ill patients. NET formation and host defense were studied during pneumonia-derived sepsis caused by in PAD4 and PAD4 mice. Patients with pneumosepsis, compared with those with nonpulmonary disease, showed increased citrullinated histone 3 (CitH3) levels in their airways and a trend toward elevated levels of NET markers cell-free DNA and nucleosomes. During murine pneumosepsis, CitH3 levels were increased in the lungs of PAD4 but not of PAD4 mice. Combined light and electron microscopy showed NET-like structures surrounding in areas of CitH3 staining in the lung; however, these were also seen in PAD4 mice with absent CitH3 lung staining. Moreover, cell-free DNA and nucleosome levels were mostly similar in both groups. Moreover, and LPS could still induce NETosis in PAD4 neutrophils. Both groups showed largely similar bacterial growth, lung inflammation, and organ injury. In conclusion, these data argue against a major role for PAD4 in NET formation, host defense, or organ injury during pneumonia-derived sepsis.
肽基精氨酸脱亚氨酶 4（PAD4）催化组蛋白的瓜氨酸化，这是中性粒细胞胞外诱捕网（NET）形成的重要步骤。我们旨在确定 PAD4 在肺炎中的作用。测量了危重病患者气道灌洗液中 NET 形成的标志物。在由肺炎相关败血症引起的 PAD4 和 PAD4 小鼠中研究了 NET 形成和宿主防御。与非肺部疾病患者相比，患有肺炎性败血症的患者其气道中瓜氨酸化组蛋白 3（CitH3）水平升高，并且 NET 标志物无细胞 DNA 和核小体的水平呈升高趋势。在鼠肺炎性败血症中，PAD4 但不是 PAD4 小鼠的肺部中 CitH3 水平升高。光镜和电子显微镜结合显示，在 CitH3 染色的肺部区域存在 NET 样结构，围绕着细菌；然而，在没有 CitH3 肺部染色的 PAD4 小鼠中也观察到了这些结构。此外，两组的无细胞 DNA 和核小体水平大多相似。此外，和 LPS 仍可诱导 PAD4 中性粒细胞的 NETosis。两组的细菌生长、肺部炎症和器官损伤基本相似。总之，这些数据表明 PAD4 在肺炎相关性败血症中的 NET 形成、宿主防御或器官损伤中没有主要作用。
