Progranulin Promotes Functional Recovery in Rats with Acute Spinal Cord Injury via Autophagy-Induced Anti-inflammatory Microglial Polarization.

Abstract

Since microglia-associated neuroinflammation plays a critical role in the progression of acute spinal cord injury, modulation of microglial activation has been suggested as a potential therapeutic strategy. Progranulin has been reported to exert neuroprotective effects by attenuating neuroinflammation, but whether these effects are due to the modulation of microglial polarization and the underlying mechanism remain unclear. Here, we investigated the effect of progranulin on microglial polarization and analyzed the crosstalk between microglial autophagy and polarization. We found that progranulin could reduce proinflammatory cytokine production at the lesion site and promote locomotor functional recovery after acute spinal cord injury. In vitro, we found that progranulin could activate microglia to acquire an anti-inflammatory phenotype and express IL-10. Moreover, progranulin-mediated enhancement of anti-inflammatory microglial polarization was attributed to the protection of lysosomal function and the enhancement of autophagic flux. Above all, progranulin exerts anti-inflammatory effects by protecting lysosomal function to enhance microglial autophagy, induce M2 microglial polarization, and ultimately improve neurological function after acute spinal cord injury. These results suggest that targeting the autophagy-lysosomal pathway to modulate microglial polarization and reduce neuroinflammation is a potential treatment for spinal cord injury.