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 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.
Subject(s)
Extracellular Vesicles , Microglia , Mice , Animals , Microglia/metabolism , Neuroinflammatory Diseases , Neurons/pathology , DNA DamageABSTRACT
How DNA damage leads to chronic inflammation and tissue degeneration with aging remains to be fully resolved. Here, we show that DNA damage leads to cellular senescence, fibrosis, loss-of-tissue architecture, and chronic pancreatitis in mice with an inborn defect in the excision repair cross complementation group 1 (Ercc1) gene. We find that DNA damage-driven R-loops causally contribute to the active release and buildup of single-stranded DNAs (ssDNAs) in the cytoplasm of cells triggering a viral-like immune response in progeroid and naturally aged pancreata. To reduce the proinflammatory load, we developed an extracellular vesicle (EV)-based strategy to deliver recombinant S1 or ribonuclease H nucleases in inflamed Ercc1−/− pancreatic cells. Treatment of Ercc1−/− animals with the EV-delivered nuclease cargo eliminates DNA damage-induced R-loops and cytoplasmic ssDNAs alleviating chronic inflammation. Thus, DNA damage-driven ssDNAs causally contribute to tissue degeneration, Ercc1−/− paving the way for novel rationalized intervention strategies against age-related chronic inflammation.
Subject(s)
DNA Repair , R-Loop Structures , Animals , Cytoplasm , DNA Damage , DNA, Single-Stranded , DNA-Binding Proteins/genetics , Endonucleases/genetics , Inflammation , MiceABSTRACT
In mammals, genome instability and aging are intimately linked as illustrated by the growing list of patients with progeroid and animal models with inborn DNA repair defects. Until recently, DNA damage was thought to drive aging by compromising transcription or DNA replication, thereby leading to age-related cellular malfunction and somatic mutations triggering cancer. However, recent evidence suggests that DNA lesions also elicit widespread epigenetic alterations that threaten cell homeostasis as a function of age. In this review, we discuss the functional links of persistent DNA damage with the epigenome in the context of aging and age-related diseases.
