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Cholesterol metabolic reprogramming mediates microglia-induced chronic neuroinflammation and hinders neurorestoration
Qiang Zhao1, Jiajian Li1, Jingjing Feng1
1Department of Neurology, Xuanwu Hospital Capital Medical University, National Center for Neurological Disorders, Beijing, China.
Abstract:
Chronic neuroinflammation is a major obstacle to post-stroke recovery, yet the underlying mechanisms, particularly the link between prolonged microglial activation and cholesterol metabolism, are not fully known. Here we show that ischaemic injury induces persistent microglial activation that perpetuates chronic inflammation, leading to microglial cholesterol accumulation and metabolic reprogramming. Using single-cell RNA sequencing, we identified distinct stroke-associated foamy microglia clusters characterized by extensive reprogramming of cholesterol metabolism. Furthermore, direct intracerebral free cholesterol or cholesterol crystal infusion recapitulated sustained microglial activation, directly linking aberrant cholesterol metabolism to prolonged neuroinflammatory responses. Therapeutically, we demonstrate that reducing microglial cholesterol overload through genetic or pharmacological activation of CYP46A1 in male mice promotes white matter repair and functional recovery. These findings highlight microglial cholesterol metabolism as a key driver of post-stroke inflammation, offering therapeutic strategies targeting cholesterol metabolism to mitigate long-term brain damage and promote neurorestoration, potentially improving stroke-related disability outcomes.
Insights
Stroke recovery is hindered by chronic neuroinflammation. This study reveals that microglial cholesterol accumulation drives this inflammation, and targeting cholesterol metabolism promotes brain repair and functional recovery in mice.
Area of Science:
- Neuroscience
- Immunology
- Metabolism
Background:
- Chronic neuroinflammation significantly impedes recovery after stroke.
- The precise mechanisms linking sustained microglial activation and cholesterol metabolism post-stroke remain unclear.
Purpose of the Study:
- To investigate the role of microglial cholesterol metabolism in chronic neuroinflammation after ischemic injury.
- To explore therapeutic strategies targeting microglial cholesterol overload for stroke recovery.
Main Methods:
- Single-cell RNA sequencing to identify stroke-associated microglial clusters.
- Intracerebral infusion of free cholesterol or cholesterol crystals to model sustained microglial activation.
- Genetic and pharmacological activation of CYP46A1 in male mice.
Main Results:
- Ischemic injury leads to persistent microglial activation, cholesterol accumulation, and metabolic reprogramming.
- Distinct foamy microglia clusters exhibit significant alterations in cholesterol metabolism pathways.
- Aberrant cholesterol metabolism directly correlates with prolonged neuroinflammatory responses.
- Reducing microglial cholesterol overload via CYP46A1 activation enhanced white matter repair and functional recovery in male mice.
Conclusions:
- Microglial cholesterol metabolism is a critical factor driving chronic neuroinflammation post-stroke.
- Targeting microglial cholesterol metabolism presents a promising therapeutic avenue for mitigating long-term brain damage and improving stroke outcomes.
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