Retinal Cells Generate and Secrete Cytokines and Bioreactive Lipids that Promote Choriocapillaris Homeostasis

Abstract

Purpose : The choriocapillaris is the primary blood supply for photoreceptors, the most numerous and metabolically demanding cells in the retina, and choriocapillaris attenuation and/or drop-out is characteristic of multiple retinal degenerative diseases. However, little is known about which cytokines and neighboring cell-types are important for maintenance of the choriocapillaris, or how cytokine dysregulation may contribute to choriocapillaris abnormalities. Here we used multiple techniques to identify cytokines and other molecules dysregulated during retinal degeneration.

Methods : Metabolomics, proteomics, and transcriptomics were used. Of the factors identified two had unknown functions in the retina (erucamide and angiogenin). We performed immunohistochemistry on human and rodent retinas (healthy and diseased) to determine which cell-types might be important for their synthesis. Both were injected into the subretinal space of rodents or overexpressed using viral vectors or electroporation to determine their function. A transgenic mouse line was generated for loss-of-function analysis for the enzyme responsible for erucamide biosynthesis (PAM).

Results : We determined that several cells in the retina are capable of secreting cytokines and bioreactive lipids that potently impact choriocapillaris function. Some of these cytokines either induce choroidal neovascularization, or have been linked to neovascular age-related macular degeneration. The cytokines include TNF-a, IL-1b, IL-6, KC/Gro from RPE/choroids and angiogenin from Muller glia. Photoreceptors secrete fatty acid amides including erucamide. Forced expression of angiogenin from Muller glia or PAM in photoreceptors, induced profound choroidal neovascularization just three days post injection. Genetic ablation of PAM in retinal neurons results in significant choriocapillaris vasodilation and profound cone photoreceptor dysfunction.

Conclusions : We will show that RPE, Muller glia, and photoreceptors all generate a unique set of signaling factors that exert profound effects on the choriocapillaris. These findings provide additional insights into the complex neurovascular interactions in the eye and may inform future gene or drug delivery-based therapies to stabilize the choriocapillaris and prevent or slow retinal degeneration, and/or provide novel targets to limit or prevent choroidal neovascularization.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.