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- Title
Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.
- Authors
Liu, Jian; Copland, David A.; Clare, Alison J.; Gorski, Mathias; Richards, Burt T.; Scott, Louis; Theodoropoulou, Sofia; Greferath, Ursula; Cox, Katherine; Shi, Gongyu; Bell, Oliver H.; Ou, Kepeng; Powell, Jenna Le Brun; Wu, Jiahui; Robles, Luis Martinez; Li, Yingxin; Nicholson, Lindsay B.; Coffey, Peter J.; Fletcher, Erica L.; Guymer, Robyn
- 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. Editor's summary: Age-related macular degeneration (AMD) progression is associated with chronic inflammation, but the role of the Myddosome complex, which is necessary for Toll-like receptor and IL-1R signaling, in AMD has not been fully elucidated. Here, Liu and colleagues identified rare variants in IRAK3, which encodes the inhibitory Myddosome component IRAK-M, as being associated with an increased risk of late AMD. Using human retinal samples and mouse models of aging and retinal injury, as well as Irak3-knockout mice, the authors showed that IRAK-M was present in retinal pigment epithelium (RPE) and decreased with age and injury. Overexpression of human IRAK3 in the RPE could attenuate outer retinal degeneration in these mouse models, suggesting a potential therapeutic strategy for AMD. —Melissa L. Norton
- Subjects
RETINAL degeneration; RHODOPSIN; MACULAR degeneration; ANIMAL models for aging; CELLULAR aging; INTERLEUKIN-1 receptor antagonist protein; PRESBYCUSIS; RETINAL injuries
- Publication
Science Translational Medicine, 2024, Vol 16, Issue 750, p1
- ISSN
1946-6234
- Publication type
Article
- DOI
10.1126/scitranslmed.adi4125