The role of prostanoids in the retina and optic nerve in health and disease.

Prostaglandin D2 (PGD2), PGE2, and other prostanoids play important roles in retinal and optic nerve (ON) health and disease, including neovascularization, neuroinflammation, and neurodegeneration. We reviewed the synthesis, expression, regulation, mechanisms, and functions of the principal prostanoids (PGF2α, PGI2, TXA2, PGE2, and PGD2) in the eye. Prostanoids can be difficult to study in-vivo or ex-vivo because they are small, unstable molecules. To address this, we incorporated lipidomics data clarifying the prostanoids present in the mouse retina and ON, and mined single-cell transcriptomic atlases of the human and mouse posterior eye to map prostanoid pathway expression across cell types. We identified species-, tissue-, and region-specific differences in prostanoid synthase and receptor expression. The PGF2α receptor (FP) was detected in mouse but not human retinal ganglion cells (RGCs). TXA2 synthase was present in ON but not retinal glia. DP2 and EP1 were enriched in microglia and astrocytes of the retrolaminar ON, but not the ON head. Analysis of mouse RGC degeneration datasets revealed dynamic regulation of prostanoid pathways in glia and RGCs. During early degeneration, macroglia upregulated PGD2 synthase (L-PGDS), while microglia upregulated the PGE2 receptor EP4. Glia downregulated intrinsic COX-1 pathways, yet we did not observe induction of COX-2. Topical NSAID treatment exacerbates RGC damage following mouse ocular hypertension, underscoring the need to clarify COX-1/2 roles in the eye. In conclusion, intrinsic prostanoid networks support retinal and ON homeostasis and are dynamically regulated in disease, representing cell-specific, receptor, and disease stage therapeutic targets, including potential RGC protection.