Mitochondrial DNA has a pro-inflammatory role in AMD
Bernard Dib1, Haijiang Lin1, Daniel E Maidana1
1Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
Abstract:
Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in the elderly of industrialized nations, and there is increasing evidence to support a role for chronic inflammation in its pathogenesis. Mitochondrial DNA (mtDNA) has been recently reported to be pro-inflammatory in various diseases such as Alzheimer's and heart failure. Here, we report that intracellular mtDNA induces ARPE-19 cells to secrete inflammatory cytokines IL-6 and IL-8, which have been consistently associated with AMD onset and progression. The induction was dependent on the size of mtDNA, but not on specific sequence. Oxidative stress plays a major role in the development of AMD, and our findings indicate that mtDNA induces IL-6 and IL-8 more potently when oxidized. Cytokine induction was mediated by STING (Stimulator of Interferon Genes) and NF-κB as evidenced by abrogation of the cytokine response with the use of specific inhibitors (siRNA and BAY 11-7082, respectively). Finally, mtDNA primed the NLRP3 inflammasome. This study contributes to our understanding of the potential pro-inflammatory role of mtDNA in the pathogenesis of AMD.
Insights
Mitochondrial DNA (mtDNA) triggers inflammatory responses in eye cells, contributing to age-related macular degeneration (AMD). Oxidized mtDNA is a potent trigger, activating key inflammatory pathways linked to AMD progression.
Area of Science:
- Ophthalmology
- Immunology
- Cell Biology
Background:
- Age-related macular degeneration (AMD) is a primary cause of irreversible blindness in older adults.
- Chronic inflammation is increasingly implicated in AMD pathogenesis.
- Mitochondrial DNA (mtDNA) is recognized as a pro-inflammatory factor in other diseases.
Purpose of the Study:
- To investigate the role of intracellular mitochondrial DNA (mtDNA) in inducing inflammatory responses relevant to AMD.
- To determine the mechanisms by which mtDNA influences cytokine secretion in retinal pigment epithelial cells.
Main Methods:
- ARPE-19 cells were treated with varying sizes and oxidation states of mtDNA.
- Cytokine levels (IL-6, IL-8) were measured.
- The involvement of STING, NF-κB, and NLRP3 inflammasome pathways was assessed using inhibitors and siRNA.
Main Results:
- Intracellular mtDNA induced ARPE-19 cells to secrete IL-6 and IL-8.
- This induction was dependent on mtDNA size and enhanced by oxidation.
- Cytokine secretion was mediated by STING and NF-κB pathways.
- mtDNA also primed the NLRP3 inflammasome.
Conclusions:
- Mitochondrial DNA, particularly when oxidized, acts as a pro-inflammatory trigger in the context of AMD.
- The STING, NF-κB, and NLRP3 inflammasome pathways are key mediators of mtDNA-induced inflammation in AMD pathogenesis.
- These findings highlight a potential therapeutic target for AMD by modulating mtDNA-related inflammation.
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