A Novel Allosteric Modulator of the IL-1 Receptor Prevents the Development of Oxygen-Induced Retinopathy

Abstract

Purpose: : Inflammatory mediators can play an important role in the progression of retinopathy of prematurity (ROP). Interleukin-1β (IL-1β) is a cytokine that modulates the expression of the anti-angiogenic Semaphorin 3A (Sema3A). We hypothesized that an augmentation of IL-1β by activated microglia induced retinal vessels damage via Sema3A activation in oxygen-induced retinopathy (OIR). We investigated whether inhibiting the actions of IL-1β using a novel allosteric modulator of IL-1 receptor (IL-1R), labelled 101.10 prevented the vaso-obliteration (VO) and subsequent pathological neovascularization (NV) associated with OIR.

Methods: : Sprague-Dawley rat pups subjected to vaso-obliteration (80% O₂ from postnatal day (P)5 to 10) and pre-retinal neovascularization (cycling O₂ during 14 days [50% and 10%] followed by room air until P18) models were treated with 101.10, IL-1Ra, or vehicle. The VO, NV and microglia activation were evaluated in retinal flat-mounts. Retinal mRNA expression was analyzed by qPCR. IL-1βsecretion in primary retinal microglia cultures subjected to hyperoxia (80% O₂) or hypoxia (4% O₂) was evaluated by ELISA. The pro-apoptotic effect of Sema3A expressed by retinal ganglion cells (RGC-5) stimulated with IL-1β was evaluated on rat endothelial cells (RBMVEC) in presence or absence of both IL-1 antagonists.

Results: : Upregulated mRNA expression of IL-1β, Sema3A and Iba-1 was detected in VO at P8 and during NV at P18. IP administration of both antagonists decreased microglial activation, IL-1β, Sema3A and Iba-1 expression and efficiently attenuated VO and pathological NV compared to vehicle. Oral administration effect of 101.10 was generally superior to that observed with oral IL-1Ra. An augmentation of IL-1β in the hyperoxic/hipoxic microglia cultures was found. Incremented release of Sema3A in RGC-5 treated with IL-1β augmented apoptosis in RBMVEC and was abolished in the presence of both IL-1 antagonists.

Conclusions: : Our findings suggest that hyperoxia/hypoxia in the retina stimulate the activation of microglial cells that produce IL-1β which exacerbates microvascular injury via Sema3A. The IL-1 antagonist, 101.10, may represent a potential new therapeutic tool for preventing the inflammatory complications of ROP and help preserve vascular beds and decrease the detrimental angiogenesis associated with this disease.

Keywords: retinopathy of prematurity • inflammation • apoptosis/cell death