Liu, Jian and Copland, David A. and Clare, Alison J. and Gorski, Mathias and Richards, Burt T. and Scott, Louis and Theodoropoulou, Sofia and Greferath, Ursula and Cox, Katherine and Shi, Gongyu and Bell, Oliver H. and Ou, Kepeng and Powell, Jenna Le Brun and Wu, Jiahui and Robles, Luis Martinez and Li, Yingxin and Nicholson, Lindsay B. and Coffey, Peter J. and Fletcher, Erica L. and Guymer, Robyn and Radeke, Monte J. and Heid, Iris M. and Hageman, Gregory S. and Chan, Ying Kai and Dick, Andrew D. (2024) Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration. SCIENCE TRANSLATIONAL MEDICINE, 16 (750): eadi4125. ISSN 1946-6234, 1946-6242
Full text not available from this repository. (Request a copy)Abstract
Chronic inflammation is a constitutive component of many age-related diseases, including age-related macular degeneration (AMD). Here, we identified interleukin-1 receptor-associated kinase M (IRAK-M) as a key immunoregulator in retinal pigment epithelium (RPE) that declines during the aging process. Rare genetic variants of IRAK3, which encodes IRAK-M, were associated with an increased likelihood of developing AMD. In human samples and mouse models, IRAK-M abundance in the RPE declined with advancing age or exposure to oxidative stress and was further reduced in AMD. Irak3-knockout mice exhibited an increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M led to a disruption in RPE cell homeostasis, characterized by compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of adeno-associated virus (AAV)-expressing human IRAK3 rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in Irak3-knockout mice. Our data show that replenishment of IRAK-M in the RPE may redress dysregulated pro-inflammatory processes in AMD, suggesting a potential treatment for retinal degeneration.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MACULAR DEGENERATION; OXIDATIVE STRESS; NLRP3 INFLAMMASOME; NEGATIVE REGULATOR; GENE-EXPRESSION; ACTIVATION; RECEPTOR; MICE; CELLS; SUSCEPTIBILITY |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Institut für Epidemiologie und Präventivmedizin > Lehrstuhl für Genetische Epidemiologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 15 Jan 2026 06:30 |
| Last Modified: | 15 Jan 2026 06:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/65400 |
Actions (login required)
 |
View Item |
