Aloe-emodin promotes remyelination by driving microglial myelin debris clearance via the CD36-PPARγ axis.

Abstract

The failure of remyelination in demyelinating diseases, such as multiple sclerosis (MS), is profoundly exacerbated by the accumulation of lipid-rich myelin debris, which sustains an inhibitory microenvironment. Efficient clearance of this debris by microglia is a critical step for myelin repair. Here, we investigated the therapeutic potential and underlying mechanisms of Aloe-emodin (AE), a natural anthraquinone, in promoting remyelination. Using a cuprizone (CPZ)-induced demyelination mouse model and primary microglial cultures, we systematically assessed the effects of AE on myelin debris clearance and structural myelin regeneration. Transcriptomic profiling (RNA-seq) and pharmacological blockade were employed to elucidate the precise molecular mechanisms. We show that in vivo administration of AE significantly accelerated behavioral recovery and structural remyelination in CPZ-intoxicated mice. Both in vitro and in vivo assays demonstrated that AE robustly enhanced microglial phagocytosis, accelerating the clearance of myelin debris. Transcriptomic analysis revealed that AE specifically reprogrammed microglia from a generalized pro-inflammatory state toward a specialized lipid-scavenging phenotype. Mechanistically, AE activated the CD36-PPARγ signaling axis to promote myelin debris clearance by microglia. Moreover, pharmacological inhibition of CD36 with sulfo-N-succinimidyl oleate (SSO) completely abolished the AE-induced microglial phagocytosis in vitro and effectively reversed the neuroprotective and pro-remyelinating benefits in vivo. Our findings identify AE as a potent pharmacological modulator that drives microglial myelin debris clearance, potentially involving the CD36-PPARγ cascade. Targeting this specific metabolic-immune axis with AE represents a highly promising therapeutic strategy for demyelinating CNS disorders.