A small molecule inhibitor of interleukin-1 receptor prevents light-induced retinal degeneration by modulating subretinal inflammation

Abstract

Purpose : To assess the effects of an IL-1 receptor inhibitor, 101.10, in modulating the inflammatory processes and the preservation of photoreceptor integrity in a model of light-induced retinal degeneration.

Methods : CD-1 mice (12-16 weeks) were exposed to blue light-emitting diode (6000 lux at 450nm) for 6 hours and then sacrificed 3 days post-illumination. Mice were intraperitoneally injected 1 hour before light exposure with 101.10 or phosphate-buffered saline and then twice a day until sacrificed. Inflammatory markers (F4/80, NLRP3, caspase-1, and IL-1β) were evaluated by Western blot or immunofluorescence in the mouse retinas. Macrophage-induced photoreceptor death was assessed ex vivo using retinal explants co-cultured with LPS-activated bone marrow-derived macrophages in the presence or absence of 101.10. Photoreceptor cell death was evaluated by TUNEL assay and caspase-3 immunoreactivity. Retinal function was assessed by flash electroretinography.

Results : 101.10 halved blue light-induced F4/80+ mononuclear phagocyte (MP) recruitment to the subretinal space. Co-localization of NLRP3, caspase-1, and IL-1β with F4/80+ MPs was detected in the subretinal space. Additionally, 101.10 prevented inflammasome and caspase-1 activation, and IL-1β formation in BLE. Retinal explants co-cultured with LPS/ATP-activated bone marrow-derived macrophages resulted in a high number of TUNEL-positive photoreceptors, which was significantly reduced by treatment with 101.10. The inhibition of the inflammatory response in vivo by 101.10 reduced caspase-3 immunoreactivity and the number of TUNEL-positive photoreceptors, and preserved retinal function in mice exposed to blue light.

Conclusions : 101.10 attenuates subretinal inflammation and preserves the integrity and function of photoreceptors in a light model of retinal degeneration. Modulation of the IL-1 receptor is a promising strategy for preserving photoreceptor integrity in ocular degenerative diseases.

This is a 2020 ARVO Annual Meeting abstract.