Regulation of neuronal lipid droplet aggregation by microglia through the lactate-lysosome signaling pathway

Abstract

Abstract Background The process of neuroinflammation is marked by the production of pro-inflammatory cytokines and leads to neuronal death. However, accumulating evidence suggests that classic inflammatory processes alone do not fully explain many aspects of neuroinflammation pathogenesis. Recent findings indicate that abnormal deposition of lipid droplet (LD) plays a crucial role in the pathogenesis of neuroinflammation. Microglia, which regulate neuronal activity have been implicated in LD aggregation during neuroinflammation. However, the regulatory mechanism of LDs in neurons remains poorly understood. Methods Neurons were stimulated with LPS-treated microglia supernatant. Immunostaining with BODIPY was used to determine the localization of LDs in different neuronal cell lines and culture systems. LAMP and LC3 were used as lysosomal markers for LD co-localization analysis. For in vivo studies, we used a sepsis-associated encephalopathy (SAE) mouse model to mimic neuroinflammation. Following microglia depletion using the small molecule CSF-1R inhibitor PLX3397, we examined lactate levels and LD changes in the mouse hippocampus. Results Our findings revealed activated microglia caused LD aggregation in neurons inducted by lactate. Furthermore, we observed co-localization of LDs with LAMP2 and LC3, suggesting involvement of the lysosomal pathway. These results were corroborated in an in vivo SAE model, where PLX3397 administration led to a reduction in LD accumulation and lactic acid levels. Conclusion Our study demonstrated that activated microglia induce LD accumulation in various neuronal cultures via the lactate-lysosome signaling pathway. A better understanding of the neuron lipid metabolism in the nervous system may ultimately contribute to the development of novel therapeutic strategies for neuroinflammation.