Abstract
Oxidative stress, inflammation, and aberrant activation of microglia in the retina are commonly observed in ocular pathologies. In glaucoma or age-related macular degeneration, the chronic activation of microglia affects retinal ganglion cells and photoreceptors, respectively, contributing to gradual vision loss. However, the molecular mechanisms that cause activation of microglia in the retina are not fully understood. Here we show that exposure of retinal pigment epithelial (RPE) cells to chronic low-level oxidative stress induces mitochondrial DNA (mtDNA)-specific damage, and the subsequent translocation of damaged mtDNA to the cytoplasm results in the binding and activation of intracellular DNA receptor Z-DNA-binding protein 1 (ZBP1). Activation of the mtDNA/ZBP1 pathway triggers the expression of proinflammatory markers in RPE cells. In addition, we show that the enhanced release of extracellular vesicles (EVs) containing fragments of mtDNA derived from the apical site of RPE cells induces a proinflammatory phenotype of microglia via activation of ZBP1 signaling. Collectively, our report establishes oxidatively damaged mtDNA as an important signaling molecule with ZBP1 as its intracellular receptor in the development of an inflammatory response in the retina. We propose that this novel mtDNA-mediated autocrine and paracrine mechanism for triggering and maintaining inflammation in the retina may play an important role in ocular pathologies. Therefore, the molecular mechanisms identified in this report are potentially suitable therapeutic targets to ameliorate development of ocular pathologies.
Highlights
Normal retina function is facilitated by an orchestrated interplay between several cell types
ARPE-19 cells were maintained for at least 3 months in medium containing 1% FBS and their differentiation was confirmed by Western blot analysis of cellular retinaldehydebinding protein 1 (CRLBP), a protein known to be associated with the vision cycle and expressed only in fully differentiated retinal pigment epithelial (RPE) cells (22)
Our studies identified a central role of oxidatively damaged mitochondrial DNA (mtDNA) and its intracellular receptor, Z-DNA binding protein 1 (ZBP1), in activation of microglia and generation of a pro-inflammatory environment in retina
Summary
Normal retina function is facilitated by an orchestrated interplay between several cell types. Activated microglia induce RPE alterations that result in an elevated chemoattractant, pro-inflammatory, and pro-angiogenic environment, which increases the recruitment and activation of immune cells, and fosters the growth of neovascular vessels into the retina. In hereditary retinopathies such as retinitis pigmentosa, chronically activated microglia are engaged in the phagocytosis of rod debris, and exacerbate photoreceptors and other adjacent cells by secretion of pro-inflammatory neurotoxic factors. RPE dysfunction, and activation of the pro-inflammatory phenotype of microglia are commonly observed in ocular pathologies. We identified a pathological role of damaged mtDNA through its interaction with the immune DNA receptor, Z-DNA binding protein 1 (ZBP1), in the development of a pathological pro-inflammatory environment in the retina, which may serve as a novel therapeutic target for ocular pathologies
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