title: Mitochondrial DNA has a pro-inflammatory role in AMD.
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.
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: Bernard
authors: B
authors: Dib
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: Haijiang
authors: H
authors: Lin
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: Daniel E
authors: DE
authors: Maidana
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: Bo
authors: B
authors: Tian
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: John B
authors: JB
authors: Miller
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: Peggy
authors: P
authors: Bouzika
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States.
authors: Joan W
authors: JW
authors: Miller
authors: Retina Service, Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, United States. Electronic address: vavvas@meei.harvard.edu.
authors: Demetrios G
authors: DG
authors: Vavvas
mesh_terms: D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D004272:DNA, Mitochondrial / Q000378:metabolism*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D015850:Interleukin-6 / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism*; D008268:Macular Degeneration / Q000378:metabolism* / Q000473:pathology; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D018384:Oxidative Stress
chemical_list: C508606:CXCL8 protein, human; D002352:Carrier Proteins; D004272:DNA, Mitochondrial; C508600:IL6 protein, human; D058847:Inflammasomes; D015850:Interleukin-6; D016209:Interleukin-8; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; C453881:NLRP3 protein, human
keywords: Age-related macular degeneration; Inflammation; Mitochondrial DNA; NLRP3 inflammasome; Retinal pigment epithelium