Antagonizing IL-1β effectively prevents inner and outer retinal degenerative changes associated with retinopathy of prematurity

Abstract

Purpose: Retinopathy of prematurity (ROP) is a serious complication in premature infants. Besides inner retina damages reported in ROP subjects, photoreceptor malfunction is also observed and appears to result from a sustained involution of the choroid - the exclusive energy source to the photoreceptors. However, mechanisms for this choroidal involution remain unexplained. Since oxidant stress associated with the pathogenesis of ROP is intertwined with inflammation, we explored the role of major pro-inflammatory cytokine, notably IL-1β, in rats subjected to Oxygen-induced retinopathy (model for ROP).

Methods: Oxygen-induced retinopathy (OIR) model was induced by exposing rat pups for the first 2 weeks of life to cycled O2 levels. Retinal and choroidal histology was performed to study thickness and integrity of microvasculature. Expression of factors of interest was studied by immunohistology, PCR, and Western blots. Finally, electroretinogram (ERG) was performed to evaluate retinal functions.

Results: OIR caused retinal vasculature damage, inner nuclear layer (INL) degeneration, and choroidal atrophy. These changes were associated with a marked increase in pro-inflammatory IL-1β, and drastic reductions in ERG responses. Early neonatal treatment with IL-1 receptor antagonist (IL-1ra [Kineret]) significantly decreased IL-1β levels attenuated INL degeneration, retinal vasoobliteration and choroidal involution. IL-1ra also curtailed expression of the anti-angiogenic factor Sema3F while promoting the expression of pro-angiogenic factor PDGF and photoreceptor protective factor PEDF. The protective effects of IL-1ra on retinal and choroidal integrity were associated with improved retinal function measured by ERG. To confirm a role for IL-1β in retinal injury associated with OIR/ROP, we injected healthy rat pups with IL-1β intravitreally; the latter reproduced salient features of OIR/ROP, including retinal vascular abnormality, INL degeneration and choroidal involution, all of which were prevented by co-administration with IL-1ra.

Conclusions: Our observations reveal a dominant role for IL-1β in inner and outer retinal damage associated with the ROP model of OIR. The findings set forth new concepts and mechanistic notions for ROP and outcome; IL-1 receptor blockers may protect the retina and sub-retina and possibly limit a progressive retinopathy that ensues from ROP.

Keywords: 706 retinopathy of prematurity • 452 choroid • 557 inflammation