Choroidal involution is associated with long-term retinal pigment epithelium (RPE) and photoreceptor dysfunction: role of IL-1β

Abstract

Purpose: Retinopathy of prematurity (ROP) is a serious complication in premature infants. Increasing survival of premature neonates has uncovered long-term disorders. Long-term retinal sequelae of ROP have also been documented. Although the inner retina is immediately impaired 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 subretinal region.<br /> Perinatal inflammation has been proposed to participate in pathological changes associated with ROP. A role for the major pro-inflammatory IL-1β on inner retinovascular disruption has been clearly demonstrated. In this report, we explored the role of IL-1β on choroidal involution and consequently on sub-retinal dysfunction in a ROP model.

Methods: Oxygen-induced retinopathy (OIR) model of ROP was induced by exposing rat pups for the first 2 weeks of life to cycling O₂ levels (between 10% and 50%). IL-1β localization were detected via immunohistochemistry. Choroidal thickness, photoreceptor and RPE density was studied in animals treated or not with IL-1β receptor antagonist. Full-field electroretinogram (ERG) and multifocal ERG were also performed to evaluate visual function.

Results: OIR was associated with an early albeit sustained involution of the choroid, a markedly hypoxic sub-retina which persisted beyond P60, a progressive loss of RPE and photoreceptors, and a functional deterioration in the retina. b-wave amplitude was diminished prior to that of the a-wave (photoreceptor function) which declined gradually to abolition by 12 months of age. IL-1β was abundantly expressed in the subretina and was associated with NLRP inflammasome activation signals, which amplifies IL-1β production. Early neonatal treatment with IL-1 receptor antagonist (IL-1ra [Kineret]) preserved choroid, prevented outer retinal hypoxia, and significantly blunted RPE and photoreceptor loss associated with OIR, while providing life-long improved a-wave amplitude.

Conclusions: Our observations suggest a critical role for IL-1b-induced choroidal degeneration leading to long-term sub- and outer-retinal disorder following OIR/ROP, as a result of marked hypoxia. Neonatal preservation of the choroid using IL-1ra, prevents long-term sub- and outer retinal anomalies that can occur following OIR/ROP.