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  • Title: Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration.
    Author: Liu J, Copland DA, Clare AJ, Gorski M, Richards BT, Scott L, Theodoropoulou S, Greferath U, Cox K, Shi G, Bell OH, Ou K, Powell JLB, Wu J, Robles LM, Li Y, Nicholson LB, Coffey PJ, Fletcher EL, Guymer R, Radeke MJ, Heid IM, Hageman GS, Chan YK, Dick AD.
    Journal: Sci Transl Med; 2024 Jun 05; 16(750):eadi4125. PubMed ID: 38838135.
    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.
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