Microglia-derived extracellular vesicles trigger age-related neurodegeneration upon DNA damage
Ermioni S. Arvanitaki, Evi Goulielmaki, Katerina Gkirtzimanaki, George Niotis, Edisona Tsakani, Electra Nenedaki, Iliana Rouska, Mary Kefalogianni, Dionysios Xydias, Ilias Kalafatakis, Sotiris Psilodimitrakopoulos, Domna Karagogeos, Björn Schumacher, Emmanuel Stratakis, George A. Garinis
Abstract
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 Er1 Cx/− 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 Er1 Cx/− 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 Er1 Cx/− mice. Together, our findings unveil a causal mechanism leading to neuroinflammation and provide a rationalized therapeutic strategy against age-related neurodegeneration.