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Introduction On March 26, 2021, the team of Professor Junwei Hao from the Department of Neurology, Xuanwu Hospital of Capital Medical University published a research paper entitled "Microglial PGC-1α protects against ischemicbrain injury by suppressing neuroinflammation" in Genome Medicine (IF: 10.
675) online.
This study reveals a new mechanism by which peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) regulates the neuroinflammatory response mediated by microglia after stroke.
Dr.
Han Bin, Dr.
Jiang Wei, and Dr.
Cui Pan are the co-first authors of the paper, and Professor Hao Junwei from the Department of Neurology, Xuanwu Hospital of Capital Medical University is the corresponding author of the paper.
Research background The latest research statistics show that there are more than 2 million new stroke patients each year, which are characterized by high morbidity, high disability and high fatality rate, of which ischemic stroke accounts for about 70%.
In the past two decades, although important progress has been made in the treatment of ischemic stroke, it still has a high disease burden.
Intravenous thrombolysis and mechanical thrombectomy are currently the most effective treatments for recanalization after ischemia, but due to the narrow time window and large limitations in use, only 3% to 5% of patients can ultimately benefit.
However, there is still a lack of evidence-based medicine for the highly used brain protective agents in clinical practice.
Therefore, exploring new interventions for ischemic stroke is a clinical problem that needs to be solved urgently.
Ischemic stroke has complex pathophysiological mechanisms, including inflammatory response, oxidative stress, calcium ion overload, mitochondrial dysfunction, etc.
The inflammatory response starts rapidly after brain injury and lasts for days, weeks, or even months.
Intervention treatment after stroke offers great possibilities.
As the central innate immune cells, microglia are the first to participate in immune and inflammatory responses.
After an ischemic stroke, microglia rapidly change in morphology and quantity and are activated.
By secreting inflammatory factors and increasing the permeability of the blood-brain barrier, it promotes the infiltration of peripheral immune cells into the lesion, thereby inducing the inflammatory cascade Reaction, and ultimately exacerbate ischemic brain damage.
Therefore, by regulating the activation of microglia and preventing the development of inflammation in the brain, it may become an effective immune regulation method for ischemic stroke.
Research Introduction The team’s previous research found that with the development of ischemic stroke, the level of PGC-1α in microglia changes dynamically, suggesting that PGC-1α may be involved in the pathophysiological process of stroke.
This study used transgenic mice that specifically regulated the overexpression or knockout of PGC-1α in microglia to explore the effect of PGC-1α on ischemic brain injury and the specific molecular mechanism.
The researchers found that mice with microglia overexpressing PGC-1α had milder neurological dysfunction.
Using a confocal microscope to scan microglia in three dimensions, the researchers found that PGC-1α can make microglia show a relatively more branched state in both physiological and pathological conditions, suggesting that PGC-1α can inhibit microglia Excessive activation of cells.
It was further confirmed by inflammatory factor protein chip analysis that PGC-1α significantly inhibited the expression of pro-inflammatory factors IL-1β, IL-6 and TNF-α in microglia.
In order to explore the specific mechanism by which PGC-1α regulates the neuroinflammatory response mediated by microglia, the researchers used chromatin immunoprecipitation sequencing combined with in vivo and in vitro functional experiments to confirm that PGC-1α interacts with the transcription factor estrogen receptor α ( ERRα) coordinately regulates the expression of autophagy-induced kinase ULK1, affects the autophagy and mitochondrial autophagy processes in microglia, thereby reducing the production of reactive oxygen species and the activation of NLRP3 inflammasomes, and inhibiting microglia-mediated neuroinflammation Response (picture).
At the same time, gene sequencing and Seahorse cell energy metabolism analysis found that PGC-1α improves the mitochondrial respiratory function of microglia.
Therefore, researchers speculate that PGC-1α may affect the energy metabolism state and cellular functions of microglia by regulating the process of autophagy and mitochondrial autophagy, thereby improving the immune and inflammatory microenvironment in the brain, and ultimately reducing ischemic brain injury .
This study revealed a new molecular mechanism for PGC-1α to regulate the function of microglia, and provides a new idea for immune regulation intervention strategies for ischemic stroke.
Figure PGC-1α regulates the mechanism of microglia-mediated neuroinflammation (Source: Public Account of Department of Neurology, Xuanwu Hospital, Capital Medical University) Expert profile Hao Junwei, Chief Physician, Professor, Doctoral Supervisor, Deputy Hospital of Xuanwu Hospital, Capital Medical University Long, director of the Department of Neurology, specializing in the diagnosis and treatment of neuroimmune diseases and cerebrovascular diseases.
In recent years, with classic autoimmune diseases of the nervous system and acute cerebrovascular diseases as the starting point, Professor Hao Junwei's team has conducted in-depth research on the pathogenic mechanisms and interventions of different forms of immune inflammation in these neurological diseases.
In this research direction, he has received funding from the National Natural Science Foundation of China (6 items) and other topics, and published more than 70 SCI articles in PNAS, J ExpMed, Genome Med, Ann Neurol, JAMA Neurol, Cell Rep, EMBO Mol Med, Stroke, etc.
Articles.
Academic part-time jobs include the Standing Committee of the Neurology Branch of the Chinese Medical Doctor Association, the member of the Neuroimmunology Group of the Neurology Branch of the Chinese Medical Association, the chairman (preparation) of the Neuroimmunology Branch of the Chinese Neuroscience Society, and the editorial board member of Translational Stroke Research.
In 2016, he was awarded the title of the first batch of Top Ten Outstanding Young Physicians in Neurology of the Chinese Medical Doctor Association.
In 2018, he was awarded the National Outstanding Youth Science Fund.
In 2020, he was awarded the Young Beijing Scholar. References: [1] Microglial PGC-1α protects against ischemicbrain injury by suppressing neuroinflammation.
Genome Medicine.
[2] Department of Neurology, Xuanwu Hospital, Capital Medical University
675) online.
This study reveals a new mechanism by which peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) regulates the neuroinflammatory response mediated by microglia after stroke.
Dr.
Han Bin, Dr.
Jiang Wei, and Dr.
Cui Pan are the co-first authors of the paper, and Professor Hao Junwei from the Department of Neurology, Xuanwu Hospital of Capital Medical University is the corresponding author of the paper.
Research background The latest research statistics show that there are more than 2 million new stroke patients each year, which are characterized by high morbidity, high disability and high fatality rate, of which ischemic stroke accounts for about 70%.
In the past two decades, although important progress has been made in the treatment of ischemic stroke, it still has a high disease burden.
Intravenous thrombolysis and mechanical thrombectomy are currently the most effective treatments for recanalization after ischemia, but due to the narrow time window and large limitations in use, only 3% to 5% of patients can ultimately benefit.
However, there is still a lack of evidence-based medicine for the highly used brain protective agents in clinical practice.
Therefore, exploring new interventions for ischemic stroke is a clinical problem that needs to be solved urgently.
Ischemic stroke has complex pathophysiological mechanisms, including inflammatory response, oxidative stress, calcium ion overload, mitochondrial dysfunction, etc.
The inflammatory response starts rapidly after brain injury and lasts for days, weeks, or even months.
Intervention treatment after stroke offers great possibilities.
As the central innate immune cells, microglia are the first to participate in immune and inflammatory responses.
After an ischemic stroke, microglia rapidly change in morphology and quantity and are activated.
By secreting inflammatory factors and increasing the permeability of the blood-brain barrier, it promotes the infiltration of peripheral immune cells into the lesion, thereby inducing the inflammatory cascade Reaction, and ultimately exacerbate ischemic brain damage.
Therefore, by regulating the activation of microglia and preventing the development of inflammation in the brain, it may become an effective immune regulation method for ischemic stroke.
Research Introduction The team’s previous research found that with the development of ischemic stroke, the level of PGC-1α in microglia changes dynamically, suggesting that PGC-1α may be involved in the pathophysiological process of stroke.
This study used transgenic mice that specifically regulated the overexpression or knockout of PGC-1α in microglia to explore the effect of PGC-1α on ischemic brain injury and the specific molecular mechanism.
The researchers found that mice with microglia overexpressing PGC-1α had milder neurological dysfunction.
Using a confocal microscope to scan microglia in three dimensions, the researchers found that PGC-1α can make microglia show a relatively more branched state in both physiological and pathological conditions, suggesting that PGC-1α can inhibit microglia Excessive activation of cells.
It was further confirmed by inflammatory factor protein chip analysis that PGC-1α significantly inhibited the expression of pro-inflammatory factors IL-1β, IL-6 and TNF-α in microglia.
In order to explore the specific mechanism by which PGC-1α regulates the neuroinflammatory response mediated by microglia, the researchers used chromatin immunoprecipitation sequencing combined with in vivo and in vitro functional experiments to confirm that PGC-1α interacts with the transcription factor estrogen receptor α ( ERRα) coordinately regulates the expression of autophagy-induced kinase ULK1, affects the autophagy and mitochondrial autophagy processes in microglia, thereby reducing the production of reactive oxygen species and the activation of NLRP3 inflammasomes, and inhibiting microglia-mediated neuroinflammation Response (picture).
At the same time, gene sequencing and Seahorse cell energy metabolism analysis found that PGC-1α improves the mitochondrial respiratory function of microglia.
Therefore, researchers speculate that PGC-1α may affect the energy metabolism state and cellular functions of microglia by regulating the process of autophagy and mitochondrial autophagy, thereby improving the immune and inflammatory microenvironment in the brain, and ultimately reducing ischemic brain injury .
This study revealed a new molecular mechanism for PGC-1α to regulate the function of microglia, and provides a new idea for immune regulation intervention strategies for ischemic stroke.
Figure PGC-1α regulates the mechanism of microglia-mediated neuroinflammation (Source: Public Account of Department of Neurology, Xuanwu Hospital, Capital Medical University) Expert profile Hao Junwei, Chief Physician, Professor, Doctoral Supervisor, Deputy Hospital of Xuanwu Hospital, Capital Medical University Long, director of the Department of Neurology, specializing in the diagnosis and treatment of neuroimmune diseases and cerebrovascular diseases.
In recent years, with classic autoimmune diseases of the nervous system and acute cerebrovascular diseases as the starting point, Professor Hao Junwei's team has conducted in-depth research on the pathogenic mechanisms and interventions of different forms of immune inflammation in these neurological diseases.
In this research direction, he has received funding from the National Natural Science Foundation of China (6 items) and other topics, and published more than 70 SCI articles in PNAS, J ExpMed, Genome Med, Ann Neurol, JAMA Neurol, Cell Rep, EMBO Mol Med, Stroke, etc.
Articles.
Academic part-time jobs include the Standing Committee of the Neurology Branch of the Chinese Medical Doctor Association, the member of the Neuroimmunology Group of the Neurology Branch of the Chinese Medical Association, the chairman (preparation) of the Neuroimmunology Branch of the Chinese Neuroscience Society, and the editorial board member of Translational Stroke Research.
In 2016, he was awarded the title of the first batch of Top Ten Outstanding Young Physicians in Neurology of the Chinese Medical Doctor Association.
In 2018, he was awarded the National Outstanding Youth Science Fund.
In 2020, he was awarded the Young Beijing Scholar. References: [1] Microglial PGC-1α protects against ischemicbrain injury by suppressing neuroinflammation.
Genome Medicine.
[2] Department of Neurology, Xuanwu Hospital, Capital Medical University
