CD36-mediated lipid-accumulation in reactive microglia drives retinal degeneration through NLRP3-IL-1β pathway

ABSTRACT: Microglia are central regulators of retinal immune homeostasis, yet their dysregulated responses can trigger neuroinflammation and drive retinal degeneration, a leading cause of irreversible blindness with limited therapeutic options. The specific pathogenic subsets and underlying mechanisms remain poorly defined. In this study, using single-cell RNA sequencing and spatial transcriptomics, we identified a distinct subset of lipid-accumulated reactive microglia (aLARM), predominantly localized to the ventral inferior retina in NaIO3-induced retinal degeneration mice, a region partially analogous to the human macula in terms of its susceptibility to neurodegenerative injury. In both patients and mouse models, this aLARM uniquely expresses high levels of CD36, which is critical for their formation and pathogenic function. Importantly, microglia-specific CD36 deletion abolished the aLARM-mediated retinal inflammation and degeneration, while subretinal transplantation of isolated CD36+ aLARM exacerbated the destruction of retinal structures and functional impairment. Furthermore, these aLARM subsets exhibited NLRP3 inflammasome activation and IL-1β production, which would activate IL-1R1 on microglia/macrophages and pericytes/ smooth muscle cells, amplifying a feed-forward inflammatory loop that worsened neurodegeneration. Finally, therapeutic blockade of CD36 using by the neutralizing antibody FA6-152 effectively reduced aLARM formationand protected against retinal degeneration. Together, our findings highlight CD36+ aLARM as a novel and targetable pathogenic microglial population that linksneuroinflammation to retinal degeneration, providing a potential foundation for microglia-based precision therapies in retinal degenerative disorders.

ORGANISM(S): Mus musculus

PROVIDER: GSE324535 | GEO | 2026/07/26

REPOSITORIES: GEO