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.
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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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