IRF3 Deficiency Promotes Retinal Senescence and Age Related Synaptic Modeling

Age-related retinal degeneration is caused by irreversible physiological process in aged people. Interferon-related factor 3 (IRF3) stimulates cell-autonomous IFN-β expression in response to age related double-stranded DNA break. However, in this study, IRF3 deficiency promotes the retinal aging process. We examined the retinas of both young adult and old WT and IRF3-/- mice, found remarkable differences of age-related phenotypes between them, including synaptic morphological changes, functional ERG alteration, increased protein level of senescence-related markers. Moreover, when IRF3 deleted, nuclear p-γH2A.X deposition and senescence-associated β-galactosidase (SA-β-gal) staining were increased in retinal layers of IRF3-/- mice, respectively. This phenomenon was blocked in the presence of G10 (an agonist of STING) administration intravitreously. In terms of H2O2 induced neuronal senescence modeling, IRF3 deletion caused increased SA-β-gal and p16INK4a expression, however, rescued by G10 administration, in vitro. In addition, extracellular signal-regulated kinases (ERK) signaling molecules increased significantly when IRF3 deleted, which may contribute to IRF3-deficiency accelerated retina senescence in both young adult and old IRF3-/- mice. Together, these results identify that IRF3 deficiency aggravate the retinal synaptic aging phenotypes of both young and old mice, promote the retinal senescence and suggest the essential role of IRF3 in maintaining the retina youthfulness. Funding: This research was supported by the National Natural Science Foundation of China (No. 81570840, No. 81371006, No. 81200926), Academician Led Science and Technological Innovation of Chongqing (cstc2017jcyj-yszxX0006) and Research Foundation of Dept. Ophthalmology in Daping Hospital, AMU (No. 9-2543). Declaration of Interest: The authors declared that there is no conflict of interest. Ethical Approval: The Institutional Animal Care and Use Committee (IACUC) of the Army Medical University approved all studies using animals.