Research, led by scientists at the Massachusetts Eye and Ear Infirmary, Harvard Medical School, has shown a mechanistic link between fragments of mitochondrial DNA (mtDNA) and the secretion of pro-inflammatory cytokines from RPE cells. The increased activity of interleukin-6 (IL-6) and interleukin-8 (IL-8) in the presence of mtDNA fragments demonstrates a possible pathway in which mitochondrial damage may feed into increased inflammation, AMD progression and choroidal neovascularization. The Harvard research additionally shows that an adaptor protein, known to play a role in DNA sensing pathways, may also mediate the mtDNA induction of the cytokines. As such, abrogating the activity of the adaptor may provide a novel therapeutic opportunity.
The research, conducted entirely on cell model systems, showed that a 2,000 base-pair fragment of mtDNA, transfected into ARPE-19 cells (a standard retinal pigment epithelium derived cell line), resulted in a 4-fold and 2-fold increase in the secretion of IL-6 and IL-8, respectively. When mtDNA was applied without a transfection agent no induction of cytokine secretion was observed, indicating that intracellular mtDNA was causing the response. While different sequences of mtDNA did not appear to have an effect on the induction of the cytokines, the size of the mtDNA did appear to make a difference – larger fragments were shown to induce stronger IL-6 and IL-8 responses. The observation of larger fragments producing stronger effects may be consistent with impaired autophagy of the RPE, characteristic of AMD. An inability to breakdown mtDNA as the system becomes compromised may then compound the problem by increasing a pro-inflammatory effect.
The authors of the study, published in Biochimica et Biophysica Acta (B. Dib et al. 1853 (2015) 2897–2906), also identified “STING” (Stimulator of Interferon Genes), as a potentially important mediator of the mtDNA induced cytokine response within ARPE cells. STING is a transmembrane endoplasmic reticulum protein previously shown to be a central player in the immune response to intracellular foreign DNA and self-DNA. Knockdown of STING function in ARPE cells using siRNA partially abrogated the mtDNA-induced IL-6 and IL-8 secretion. STING has also been shown to stimulate the NF-κB pathway which itself promotes choroidal neovascularization. Consequently, targeting of STING may dampen two or more strands of the pro-inflammatory pathways operating in AMD pathogenesis.