胆红素通过调控小胶质细胞表型转化改善慢性缺血性脑白质损伤OA

Objective:To investigate the protective effects of bilirubin on white matter injury and cognitive impairment under chronic cerebral hypoperfusion,and to elucidate its association with the regulation of microglial functional states.Methods:A bilateral common carotid artery stenosis(BCAS)mouse model was employed to induce chronic cerebral hypoperfusion.Behavioral assessments,histological analyses,and single-cell transcriptomic profiling were integrated to systematically evaluate the effects of bilirubin on white matter integrity and the inflammatory microenvironment.Results:Bilirubin treatment significantly improved learning,memory,and recognition abilities in BCAS mice,accompanied by marked attenuation of demyelination and structural disruption in the corpus callosum.Single-cell transcriptomic and histological analyses revealed that bilirubin suppressed inflammatory and immune-response-related transcriptional programs,thereby inhibiting the inflammatory and phagocytic activation of microglia.Trajectory inference and transcription factor regulatory analyses demonstrated that bilirubin redirected microglial state transitions away from inflammation-associated terminal states toward homeostatic and repair-related phenotypes.This shift was characterized by enhanced TGF-β-associated regulatory networks and concurrent suppression of interferon signaling pathways.Conclusion:Bilirubin effectively alleviates white matter injury and cognitive dysfunction induced by chronic cerebral hypoperfusion by reshaping microglial functional states and the inflammatory microenvironment.