RAD51 stabilizes neutrophil extracellular traps to compartmentalize inflammation

• 成果类型: Article
• 署名作者: Tsansizi, Lorenza Iolanda; Guan, Sophie Yihan; Aramburu, Iker Valle; Punatar, Rajvee Shah; Williams, Thomas J.; Qiao, Yihe E.; Reed, Anna; Armstrong-James, Darius; West, Stephen C.; Papayannopoulos, Venizelos
• 署名单位: Francis Crick Institute; Francis Crick Institute; Imperial College London; Guy's & St Thomas' NHS Foundation Trust; Imperial College London; Royal Brompton Hospital; Guy's & St Thomas' NHS Foundation Trust; Royal Brompton & Harefield NHS Foundation Trust; Harefield Hospital
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aed9286
• 发表日期: 2026-08-20
• 页码: eaed9286
• 关键词: homologous recombination; cytokine production; REPEATED EXPOSURE; MYELOPEROXIDASE; differentiation; degradation; macrophages; mechanism; elastase; immunity

摘要

Neutrophil extracellular traps (NETs) feature a branched chromatin architecture whose origin and function remain unknown. We found that NET branching is mediated by RAD51, a protein generating DNA junctions during DNA recombination repair. Pharmacological inhibition, RAD51 knockdown, or GEN1 and RuvC resolvase treatment reduced branching and destabilized NETs, whereas RAD51 up-regulation by different stimuli generated NETs with variable stability. RAD51 inhibition during murine pulmonary Aspergillus fumigatus infection dismantled NETs and reduced lung cytokines. However, the increased accumulation of NET components in the circulation led to interleukin-6 (IL-6) induction in circulating monocytes that exacerbated type 2 inflammation and asthma. Extracellular plasma DNA correlated with IL-6 and eotaxin in human aspergillosis. By structurally stabilizing NETs, RAD51 compartmentalizes inflammation to thwart aberrant systemic immune activation, linking DNA repair to inflammation.