CD36-mediated lipid-accumulation in reactive microglia contributes to retinal degeneration via the NLRP3-IL-1β pathway in mice.

Microglia are central regulators of retinal immune homeostasis, yet their pathogenic states in retinal degeneration remain less well understood. Here we identified a distinct subset of lipid-accumulated reactive microglia (aLARM), using scRNA sequencing and spatial transcriptomics in NaIO3-induced retinal degeneration mice, predominantly localized to the outer retina. aLARM were conserved across mouse models and patients and uniquely marked by high CD36 expression. Microglia-specific CD36 deletion abolished aLARM-mediated inflammation and degeneration, whereas subretinal transplantation of CD36+ aLARM exacerbated retinal structural destruction and functional impairment. Mechanistically, CD36+ aLARM activated NLRP3 inflammasome and produced IL-1β, engaging IL-1R1 on microglia/macrophages and pericytes/SMCs to amplify a feed-forward inflammatory circuit. Therapeutic CD36 blockade with the neutralizing antibody FA6-152 reduced aLARM formation and protected against neurodegeneration. Together, our findings highlight CD36+ aLARM as a targetable pathogenic microglial population linking neuroinflammation to retinal degeneration, providing a potential foundation for microglia-based precision therapies.