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Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration

Liu, Jian; Copland, David A; Clare, Alison J; Gorski, Mathias; Richards, Burt T; Scott, Louis; Theodoropoulou, Sofia; ... Dick, Andrew D; + view all (2024) Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration. Science Translational Medicine , 16 (750) , Article eadi4125. 10.1126/scitranslmed.adi4125. Green open access

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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.

Type: Article
Title: Replenishing IRAK-M expression in retinal pigment epithelium attenuates outer retinal degeneration
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1126/scitranslmed.adi4125
Publisher version: http://dx.doi.org/10.1126/scitranslmed.adi4125
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
Keywords: Retinal Pigment Epithelium, Interleukin-1 Receptor-Associated Kinases, Animals, Humans, Mice, Knockout, Retinal Degeneration, Oxidative Stress, Mice, Cellular Senescence, Mice, Inbred C57BL, Macular Degeneration, Mitochondria, Male
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery.ucl.ac.uk/id/eprint/10193300
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