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Oxidative stress induces Z-DNA-binding protein 1-dependent activation of microglia via mtDNA released from retinal
Jamal Saada1, Ryan J McAuley2, Michela Marcatti3
1Department of Ophthalmology and Visual Sciences, University of Texas Medical Branch, Galveston, Texas, USA; Department of Anesthesiology, University of Texas Medical Branch, Galveston, Texas, USA.
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.
Insights
Oxidatively damaged mitochondrial DNA (mtDNA) activates Z-DNA-binding protein 1 (ZBP1) in retinal cells, driving inflammation in ocular diseases like glaucoma and AMD. This discovery reveals a new therapeutic target for vision loss.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Ocular pathologies like glaucoma and age-related macular degeneration involve retinal inflammation and microglial activation, leading to vision loss.
- The precise molecular triggers for microglial activation in the retina remain incompletely understood.
Purpose of the Study:
- To elucidate the molecular mechanisms underlying retinal inflammation and microglial activation in ocular pathologies.
- To identify novel signaling pathways and potential therapeutic targets for vision-threatening conditions.
Main Methods:
- Investigated the effects of chronic low-level oxidative stress on retinal pigment epithelial (RPE) cells.
- Examined mitochondrial DNA (mtDNA) damage and its translocation to the cytoplasm.
- Assessed the role of Z-DNA-binding protein 1 (ZBP1) in mediating inflammatory responses.
- Analyzed extracellular vesicles (EVs) containing mtDNA fragments and their impact on microglial activation.
Main Results:
- Chronic oxidative stress in RPE cells caused mtDNA damage and cytoplasmic translocation, activating ZBP1.
- Activated ZBP1 triggered proinflammatory marker expression in RPE cells.
- Extracellular vesicles containing damaged mtDNA induced a proinflammatory microglial phenotype via ZBP1 activation.
Conclusions:
- Oxidatively damaged mtDNA acts as a signaling molecule, with ZBP1 as its intracellular receptor, initiating retinal inflammation.
- A novel mtDNA-mediated autocrine and paracrine mechanism contributes to sustained retinal inflammation in ocular diseases.
- Targeting the mtDNA/ZBP1 pathway presents a potential therapeutic strategy for ocular pathologies and vision loss.
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