ORIGINAL RESEARCH article
Front. Immunol.
Sec. Inflammation
Volume 16 - 2025 | doi: 10.3389/fimmu.2025.1608428
This article is part of the Research TopicInteractions Between Autophagy and Immune Response: Cell Communication and Disease ImplicationsView all 7 articles
Molecular and Subcellular Mechanisms of Vital Macrophage Extracellular Trap Formation
Provisionally accepted
- Feinstein Institute for Medical Research, New York, New York, United States
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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.
Keywords: macrophage, extracellular trap, MetS, Vital, Gasdermin D, Autophagy, LC3 secretory lysosome, ESCRT
Received: 08 Apr 2025; Accepted: 26 Jun 2025.
Copyright: © 2025 Lee, Brenner, Aziz and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Max Brenner, Feinstein Institute for Medical Research, New York, 11030, New York, United States
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