重要巨噬细胞胞外诱捕网形成的分子和亚细胞机制。
Molecular and subcellular mechanisms of vital macrophage extracellular trap formation.
作者信息
Lee Yongchan, Brenner Max, Aziz Monowar, Wang Ping
机构信息
Center for Immunology and Inflammation, The Feinstein Institutes for Medical Research, Manhasset, NY, United States.
Departments of Surgery and Molecular Medicine, Zucker School of Medicine, Manhasset, NY, United States.
出版信息
Front Immunol. 2025 Jul 31;16:1608428. doi: 10.3389/fimmu.2025.1608428. eCollection 2025.
Macrophage extracellular traps (METs) are a poorly understood process beneficial for infection control but detrimental in inflammation, autoimmunity and cancer. Our research shows that viable macrophages release METs even when plasma membrane lysis is blocked. We demonstrate, for the first time, that nuclear DNA is extruded directly into the cytoplasm through Gasdermin D pores on the nuclear envelope. Gasdermin D pore formation was triggered by extracellular cold-inducible RNA-binding protein, which activates the TLR4 signal transduction pathway. This DNA is processed in the cytoplasm, enters the vesicular transport system aided by autophagic flux and the Endosomal Sorting Complex. The DNA then enters the lysosomal compartment, where it undergoes histone 3 citrullination, forms nascent traps containing myeloperoxidase, and is released to the extracellular space. Our study provides valuable insights into vital MET formation and its mechanism that will enable future studies on the role of METs in health and disease.
巨噬细胞胞外诱捕网(METs)是一个尚不清楚的过程,它对感染控制有益,但在炎症、自身免疫和癌症中却是有害的。我们的研究表明,即使质膜裂解被阻断,活的巨噬细胞也会释放METs。我们首次证明,核DNA通过核膜上的Gasdermin D孔直接挤出到细胞质中。Gasdermin D孔的形成是由细胞外冷诱导RNA结合蛋白触发的,该蛋白激活TLR4信号转导通路。这种DNA在细胞质中被加工,在自噬通量和内体分选复合体的帮助下进入囊泡运输系统。然后,DNA进入溶酶体区室,在那里它经历组蛋白3瓜氨酸化,形成含有髓过氧化物酶的新生诱捕网,并释放到细胞外空间。我们的研究为重要的MET形成及其机制提供了有价值的见解,这将有助于未来对METs在健康和疾病中的作用进行研究。
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