Inhibition of Autophagy-Lysosomal Function Exacerbates Microglial and Monocyte Lipid Metabolism Reprogramming and Dysfunction After Brain Injury

The study investigates the effects of traumatic brain injury (TBI) on lipid metabolism in the brain using a mouse model. It reveals that TBI leads to significant reprogramming of lipid metabolism in microglial and monocyte populations, resulting in the accumulation of neutral storage lipids like cholesteryl esters and triglycerides. These lipids accumulate in lysosomes and are linked to lysosomal dysfunction and inhibited autophagy. The study finds that this lipid accumulation is due to altered lipid handling, triggered by the phagocytosis of lipid-rich myelin debris. Furthermore, mice with autophagy defects in microglia and monocytes show exacerbated lipid metabolism reprogramming and lipid accumulation, suggesting a pathological feedback loop where lipid phagocytosis inhibits autophagy-lysosomal function, worsening lipid retention, reprogramming, and inflammation.