Replenishing Age-Related Decline of IRAK-M Expression in Retinal Pigment Epithelium Attenuates Outer Retinal Degeneration
Liu, J.; Copland, D. A.; Clare, A. J.; Gorski, M.; Richards, B. T.; Scott, L.; Theodoropoulou, S.; Greferath, U.; Cox, K.; Bell, O. H.; Ou, K.; Powell, J. L. B.; Wu, J.; Martinez Robles, L.; Li, Y.; Nicholson, L. B.; Coffey, P. J.; Fletcher, E. L.; Guymer, R.; Radeke, M. J.; Heid, I. M.; Hageman, G. S.; Chan, Y. K.; Dick, A. D.
Show abstract
Unchecked, chronic inflammation is a constitutive component of age-related diseases, including age-related macular degeneration (AMD). Here we identified interleukin-1 receptor-associated kinase (IRAK)-M as a key immunoregulator in retinal pigment epithelium (RPE) that declines with age. Rare genetic variants of IRAK-M increased the likelihood of AMD. IRAK-M expression in RPE declined with age or oxidative stress and was further reduced in AMD. IRAK-M-deficient mice exhibited increased incidence of outer retinal degeneration at earlier ages, which was further exacerbated by oxidative stressors. The absence of IRAK-M disrupted RPE cell homeostasis, including compromised mitochondrial function, cellular senescence, and aberrant cytokine production. IRAK-M overexpression protected RPE cells against oxidative or immune stressors. Subretinal delivery of AAV-expressing IRAK-M rescued light-induced outer retinal degeneration in wild-type mice and attenuated age-related spontaneous retinal degeneration in IRAK-M- deficient mice. Our data support that replenishment of IRAK-M expression may redress dysregulated pro-inflammatory processes in AMD, thereby treating degeneration. One Sentence SummaryIRAK-M is a protective molecule and promising therapeutic target for macular degeneration
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