Microglial PGC-1α protects against ischemic brain injury by suppressing neuroinflammation

Genome Medicine

Chun Dang¹  He Li¹  Wei Jiang¹  Pan Cui¹  Kai Zheng¹  Lin Chen¹  Junjie Wang¹  Bin Han²  Junwei Hao²  Zhenyu Ju³  Rongxin Zhang⁴  Qing Mei Wang⁵ 

[1] Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 300052, Tianjin, China;Department of Neurology, Xuanwu Hospital, Capital Medical University, 100053, Beijing, China;Department of Neurology, Tianjin Neurological Institute, Tianjin Medical University General Hospital, 300052, Tianjin, China;Key Laboratory of Regenerative Medicine of Ministry of Education, Institute of Aging and Regenerative Medicine, Jinan University, 510632, Guangzhou, China;Laboratory of Immunology and Inflammation, Department of Immunology and Research Center of Basic Medical Sciences, Key Laboratory of Immune Microenvironments and Diseases of Educational Ministry, Tianjin Medical University, 300070, Tianjin, China;Stroke Biological Recovery Laboratory, Department of Physical Medicine and Rehabilitation, Spaulding Rehabilitation Hospital, the teaching affiliate of Harvard Medical School Charlestown, 02129, Boston, MA, USA;

关键词: Microglia;    Neuroinflammation;    PGC-1α;    Ischemic stroke;   

DOI  :  10.1186/s13073-021-00863-5

来源: Springer

【 摘 要 】

BackgroundNeuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS). PPARγ coactivator-1α (PGC-1α), as a master coregulator of gene expression in mitochondrial biogenesis, was found to be transiently upregulated in microglia after AIS. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown.MethodsPGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Downstream inflammatory cytokine production and NLRP3 activation were also determined. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke.ResultsPGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α.ConclusionsMechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.

【 授权许可】

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