Activation of choroidal mast cells partakes in retinal inflammation and degeneration under oxidative-stress conditions

Neuroinflammation is a hallmark of retinal neurodegeneration, yet the early triggers that convert localized tissue stress into a chronic inflammatory cascade remain poorly defined. While microglia and macrophages have been extensively studied, the contribution of mast cells, highly potent tissue-resident modulators, remains unclear. Here, we demonstrate that mast cells are key regulators of the myeloid inflammatory response that links initial RPE stress to chronic retinal degeneration. Using a mouse model of retinal injury, we identify early mast cell activation as a key event preceding photoreceptor loss. Genetic ablation or pharmacological stabilization of mast cells attenuated inflammation, preserved photoreceptor survival, and maintained retinal function. Mechanistically, scRNA-seq analysis revealed that mast cell deficiency fundamentally reprograms the retinal immune microenvironment, specifically by limiting a pro-inflammatory monocyte signature. We further identify mast cell-derived tryptase as a principal effector driving these inflammatory responses. These results highlight a pivotal role for mast cells in the pathogenesis of retinal degeneration and suggest that targeting these cells provides a viable, clinically actionable strategy for managing AMD.