We showed that microglial PGC-1α overexpression could inhibit the neuroinflammatory responses induced by ischemic brain injury. In this study, we found that PGC-1α expression changed in microglia from stroke patients and a mouse model of AIS. However, the role of PGC-1α in microglia in the modulation of poststroke neuroinflammation remains poorly understood. In primary human astrocytes, PGC-1α markedly suppresses oxidative damage and the generation of proinflammatory mediators. In addition, PGC-1α was shown to attenuate MPTP-induced neurodegenerative processes in a Parkinson’s disease (PD) model by upregulating mitochondrial antioxidants, such as GPx1 and SOD2, thereby reducing ROS production. In multiple sclerosis patients, reduced PGC-1α expression was accompanied by decreased expression of mitochondrial antioxidants and uncoupling proteins (UCPs), thereby leading to neuronal loss and neurodegeneration. In addition, PGC-1α has been shown to play a crucial role in various neurological disorders by modulating mitochondrial function and reactive oxygen species (ROS) levels. Peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master coregulator that governs gene expression during mitochondrial biogenesis by interacting with many transcription factors, such as estrogen-related receptor α (ERRα), which also serves as an important coordinator and is involved in the transcriptional regulation of many physiological processes. Therefore, selective regulation of microglial activation can strongly suppress brain inflammation. Activated microglia promote the infiltration of peripheral leukocytes by releasing proinflammatory cytokines and engulfing adjacent blood vessels. After stroke, microglia act as the earliest immune responders, substantially contributing to the initiation and propagation of neuroinflammation. Microglia play crucial roles under both physiological and pathological conditions, such as immune surveillance and response to brain injury. Many preclinical and clinical studies on stroke have suggested that immune modulation in the central nervous system (CNS) could be a viable alternative treatment strategy for AIS. The neuroinflammation and immune responses occurring minutes to hours after stroke were associated with the complex pathology of brain injury after AIS. Unfortunately, effective therapies for AIS remain limited to date. Our findings indicate that microglial PGC-1α may be a promising therapeutic target for AIS.Īcute ischemic stroke (AIS) accounts for the majority of catastrophic disabilities and deaths among individuals with cerebrovascular disorders. Mechanistically, in AIS, PGC-1α promotes autophagy and mitophagy through ULK1 and reduces NLRP3 activation. Pharmacological inhibition or knockdown of ULK1 expression impaired autophagic/mitophagic activity, thus abolishing the neuroprotective effects of PGC-1α. More specifically, the autophagic clearance of mitochondria was enhanced by PGC-1α regulation, indicating the important role of mitophagy. PGC-1α significantly promoted autophagic flux and induced autolysosome formation. ChIP-Seq analysis and KEGG pathway analysis revealed that mitophagy was significantly enhanced. Microglia-specific PGC-1α overexpressing mice exhibited significantly decreased neurologic deficits after ischemic injury, with reduced NLRP3 activation and proinflammatory cytokine production. PGC-1α expression was shortly increased after ischemic stroke, not only in human brain samples but also in mouse brain samples. Finally, pharmacological inhibition and genomic knockdown of ULK1 were performed to estimate the role of ULK1 in mediating mitophagic activity after ischemic stroke. Unc-51-like autophagy activating kinase 1 (ULK1) expression was evaluated under the PGC-1α interaction with ERRα. Autophagic and mitophagic activity was further monitored by immunofluorescence staining. ChIP-Seq analysis was performed to detect PGC-1α-binding sites in microglia. Downstream inflammatory cytokine production and NLRP3 activation were also determined. The morphology and gene expression profile of microglia with PGC-1α overexpression were evaluated. Subsequently, we employed transgenic mice with microglia-specific overexpression of PGC-1α for middle cerebral artery occlusion (MCAO). PGC-1α expression in microglia from human and mouse brain samples following ischemic stroke was first determined. However, the role of microglial PGC-1α in poststroke immune modulation remains unknown. 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.
Neuroinflammation and immune responses occurring minutes to hours after stroke are associated with brain injury after acute ischemic stroke (AIS).
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