The role of IL-1β in progressive retinal degeneration associated with retinopathy of prematurity

Abstract

Purpose: Retinopathy of prematurity (ROP) is a serious complication in premature infants. With the use of surfactant began in late 1980’s, most premature neonates now survive and live into adulthood. Besides immediate damages on the inner retina in ROP, progressive photoreceptor malfunction is also observed, and appears to result from a sustained involution of the choroid, the exclusive source of O2 and nutrients to the photoreceptors. Sustained choroidal involution has been reported both in clinics and in the established animal model of O2-induced retinopathy (OIR). However, mechanisms for this choroidal involution remain unexplained. While inflammation has often been proposed in pathogenesis of ROP/OIR, the specific role of pro-inflammatory cytokines in the neonatal sub-retina has yet to be explored. Therefore, we investigated the role of the major pro-inflammatory cytokine, notably IL-1β, in rats subjected to OIR.

Methods: Oxygen-induced retinopathy was achieved by exposing rat pups to cycling O2 levels. Retinal and choroidal histology were performed to study the thickness and integrity of microvasculature. Expression of factors of interest was studied by immunohistology, PCR, and Western blots. Finally, full-field and multifocal electroretinograms (ERG) were performed to evaluate visual function.

Results: Our longitudinal study revealed that OIR caused sustained outer and sub-retinal hypoxia, and a progressive deterioration of the sub-retina including an increase in abnormal mitochondria in RPE cells, gradual degeneration of photoreceptor and ensuing decline in visual function (ERG). These changes were associated with marked increases in pro-inflammatory IL-1β, and drastic reductions in photoreceptor response. Early neonatal treatment with IL-1 receptor antagonist (IL-1ra [Kineret]) significantly decreased IL-1β levels and attenuated choroidal involution. Moreover, IL-1ra effectively blunted long-term photoreceptor loss induced by OIR. This amelioration in outer retinal structure by IL-1ra was associated with improved retinal function (ERG).

Conclusions: Our observations reveal a dominant role for IL-1β in outer retinal damage associated with the ROP model. Our findings set forth new mechanism notion of ROP and its long-term outcomes in adults. IL-1 receptor blockers (administered early in the neonate) may be protective to the retina and consequently limit progressive deterioration initiated by ROP.

Keywords: 706 retinopathy of prematurity • 557 inflammation • 414 aging: visual performance