Microglia- derived extracellular vesicles trigger age- related neurodegeneration upon DNA damage

• 成果类型: Article
• 署名作者: Arvanitaki, Ermioni S.; Goulielmaki, Evi; Gkirtzimanaki, Katerina; Niotis, George; Tsakani, Edisona; Nenedaki, Electra; Rouska, Iliana; Kefalogianni, Mary; Xydias, Dionysios; Kalafatakis, Ilias; Psilodimitrakopoulos, Sotiris; Karagogeos, Domna; Schumacher, Bjoern; Stratakis, Emmanuel; Garinis, George A.
• 署名单位: University of Crete; Foundation for Research & Technology - Hellas (FORTH); University of Crete; Foundation for Research & Technology - Hellas (FORTH); University of Crete; University of Crete; University of Cologne; University of Cologne
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-13272
• DOI: 10.1073/pnas.2317402121
• 发表日期: 2024-04-23
• 关键词: oxidative damage; inflammation; repair; mechanisms; senescence; exosomes; deficiency; expression; ercc1-xpf; reveals

摘要

DNA damage and neurodegenerative disorders are intimately linked but the underlying mechanism remains elusive. Here, we show that persistent DNA lesions in tissue- resident macrophages carrying an XPF-ERCC1 DNA repair defect trigger neuroinflammation and neuronal cell death in mice. We find that microglia accumulate dsDNAs and chromatin fragments in the cytosol, which are sensed thereby stimulating a viral - like immune response in Er1Cx/- and naturally aged murine brain. Cytosolic DNAs are packaged into extracellular vesicles (EVs) that are released from microglia and discharge their dsDNA cargo into IFN- responsive neurons triggering cell death. To remove cytosolic dsDNAs and prevent inflammation, we developed targeting EVs to deliver recombinant DNase I to Er1Cx/- brain microglia in vivo. We show that EV- mediated elimination of cytosolic dsDNAs is sufficient to prevent neuroinflammation, reduce neuronal apoptosis, and delay the onset of neurodegenerative symptoms in Er1Cx/- mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age- related neurodegeneration.