PLXNA2 knockdown promotes M2 microglia polarization through mTOR/STAT3 signaling to improve functional recovery in rats after cerebral ischemia/reperfusion injury

Li, Sisi; Hua, Xu‐Yun; Zheng, Mou‐Xiong; Wu, Jiajia; Ma, Zhenzhen; Xing, Xiang‐Xin; Ma, Jie; Zhang, Junpeng; Shan, Chunlei; Xu, Jian‐Guang

doi:10.1016/j.expneurol.2021.113854

Cited by 35 publications

(21 citation statements)

References 62 publications

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“…21,47 Besides, our results support the hypothesis that downregulation of inflammatory processes correlates with improved recovery of function and that M1 polarized microglia play a more detrimental role—while M2 polarized microglia are more supportive in tissue reorganization and functional recovery after stroke. 23,48-51 We could non-invasively verify our findings on cellular responses after tDCS by PET-imaging on day 21, which qualitatively confirmed our ex vivo results as one of the keys to a successful clinical translation in the future. 40,44 However, future PET studies should be performed at earlier times post-stroke for visualization of neuroinflammation.…”

Section: Discussionsupporting

confidence: 79%

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery

Walter

Pikhovych

Endepols

et al. 2022

Neurorehabil Neural Repair

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Background Transcranial direct current stimulation (tDCS) promotes recovery after stroke in humans. The underlying mechanisms, however, remain to be elucidated. Animal models suggest tDCS effects on neuroinflammation, stem cell proliferation, neurogenesis, and neural plasticity. Objective In a longitudinal study, we employed tDCS in the subacute and chronic phase after experimental focal cerebral ischemia in mice to explore the relationship between functional recovery and cellular processes. Methods Mice received photothrombosis in the right motor cortex, verified by Magnetic Resonance Imaging. A composite neuroscore quantified subsequent functional deficits. Mice received tDCS daily: either 5 sessions from day 5 to 9, or 10 sessions with days 12 to 16 in addition. TDCS with anodal or cathodal polarity was compared to sham stimulation. Further imaging to assess proliferation and neuroinflammation was performed by immunohistochemistry at different time points and Positron Emission Tomography at the end of the observation time of 3 weeks. Results Cathodal tDCS at 198 kC/m2 (220 A/m2) between days 5 and 9 accelerated functional recovery, increased neurogenesis, decreased microglial activation, and mitigated CD16/32-expression associated with M1-phenotype. Anodal tDCS exerted similar effects on neurogenesis and microglial polarization but not on recovery of function or microglial activation. TDCS on days 12 to 16 after stroke did not induce any further effects, suggesting that the therapeutic time window was closed by then. Conclusion Overall, data suggest that non-invasive neuromodulation by tDCS impacts neurogenesis and microglial activation as critical cellular processes influencing functional recovery during the early phase of regeneration from focal cerebral ischemia.

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Section: Discussionsupporting

confidence: 79%

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery

Walter

Pikhovych

Endepols

et al. 2022

Neurorehabil Neural Repair

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“…Under the stimulation of LPS and IFN-γ, microglia were activated as M1 phenotype, releasing M1-related markers CD86, iNOS, and M1-related in ammatory cytokines IL-1β, IL-6, TNF-α and MCP-1. In response to the stimulation of IL-4, IL-10 and IL-13, microglia activate to the M2 phenotype, releasing M2-related markers ARG-1 and CD206 as well as m2-related antiin ammatory cytokines TGF-β and IL-10 (Li et al, 2021a). The functional differences between M1 and M2 microglias are closely related to central nervous system diseases, so it is very important to regulate the M1/M2 balance of microglia.…”

Section: Introductionmentioning

confidence: 99%

Castor1 overexpression regulates microglia M1/M2 polarization via inhibiting mTOR pathway

Huang

et al. 2022

Metab Brain Dis

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Microglia are resident immune cells in the brain and are closely associated with central nervous system in ammation and neurodegenerative diseases. It is known that mTOR pathway plays an important role in the polarization of microglia. Castor1 has been identi ed as the cytosolic arginine sensor for the mTORC1 pathway, but the role of Castor1 in microglial polarization is still unknown. The purpose of this study was to explore the regulatory effect of Castor1 on microglial polarization and the underlying mechanism. The results demonstrated that Castor1 expression was signi cantly decreased in LPS and IFNγ treated microglia. Castor1 overexpression inhibited the microglia M1 polarization by reducing the expression of M1 related markers. However, microglia M2 polarization was promoted when Castor1 was overexpressed in IL-4 treated microglia. Mechanistically, Castor1 overexpression inhibited the activation of mTOR signaling pathway. In addition, after treatment with the mTOR activator MHY1485, the inhibitory effect of Castor1 overexpression on M1 polarization was attenuated, indicating that the regulation effects of Castor1 on M1 polarization was dependent on its inhibition of mTOR pathway. We propose that Castor1-mTOR signaling pathway could be considered as a potential target for treatment and intervention of central nervous system-related diseases by regulating microglia polarization.

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“…At the molecular level, mechanisms of neuroinflammation have been unraveled in the last few years by ex vivo transcriptomic comparisons of microglial subpopulations (or single cells) dissociated after micro-dissection of the damaged brain regions in experimental animal models of disease or injuries at critical stages, as compared to analogous samples coming from the respective controls. Microglia was purified from primary cell suspensions by fluorescence-activated cell sorter (FACS) using for instance CD11b-fluorescent immunolabeling, and subjected to RNA-sequencing ( Keren-Shaul et al, 2017 ; Krasemann et al, 2017 ; Madore et al, 2020 ; Masuda et al, 2020b ; Li et al, 2021 ; Liu et al, 2021 ; Lu et al, 2021 ; Muzio et al, 2021 ; Yusuying et al, 2021 ). The key results of these approaches are summarized in Table 1 to facilitate comparison between the different pathological contexts of neuroinflammation.…”

Section: Neuroinflammation: the Innate Immune Reaction Of The Central...mentioning

confidence: 99%

“… Summarized from (i) Li et al, 2021 ; Liu et al, 2021 ; Lu et al, 2021 ; Yusuying et al, 2021 (for ischemia-reperfusion), (ii) Keren-Shaul et al, 2017 ; Krasemann et al, 2017 ; Butovsky and Weiner, 2018 ; Madore et al, 2020 (for Alzheimer’disease and amyotrophic lateral sclerosis), (iii) Muzio et al, 2021 (for aging); (iv) Madore et al, 2020 ; Li et al, 2021 (for Parkinson’s disease). Bold-italic: messengers secreted by microglial cells.…”

Section: Neuroinflammation: the Innate Immune Reaction Of The Central...mentioning

confidence: 99%

Neuroinflammation: A Possible Link Between Chronic Vascular Disorders and Neurodegenerative Diseases

Moyse

Krantic

Djellouli

et al. 2022

Front. Aging Neurosci.

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Various age-related diseases involve systemic inflammation, i.e. a stereotyped series of acute immune system responses, and aging itself is commonly associated with low-grade inflammation or inflamm’aging. Neuroinflammation is defined as inflammation-like processes inside the central nervous system, which this review discusses as a possible link between cardiovascular disease-related chronic inflammation and neurodegenerative diseases. To this aim, neuroinflammation mechanisms are first summarized, encompassing the cellular effectors and the molecular mediators. A comparative survey of the best-known physiological contexts of neuroinflammation (neurodegenerative diseases and transient ischemia) reveals some common features such as microglia activation. The recently published transcriptomic characterizations of microglia have pointed a marker core signature among neurodegenerative diseases, but also unraveled the discrepancies with neuroinflammations related with acute diseases of vascular origin. We next review the links between systemic inflammation and neuroinflammation, beginning with molecular features of respective pro-inflammatory cells, i.e. macrophages and microglia. Finally, we point out a gap of knowledge concerning the atherosclerosis-related neuroinflammation, which is for the most surprising given that atherosclerosis is established as a major risk factor for neurodegenerative diseases.

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PLXNA2 knockdown promotes M2 microglia polarization through mTOR/STAT3 signaling to improve functional recovery in rats after cerebral ischemia/reperfusion injury

Cited by 35 publications

References 62 publications

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery

Transcranial-Direct-Current-Stimulation Accelerates Motor Recovery After Cortical Infarction in Mice: The Interplay of Structural Cellular Responses and Functional Recovery

Castor1 overexpression regulates microglia M1/M2 polarization via inhibiting mTOR pathway

Neuroinflammation: A Possible Link Between Chronic Vascular Disorders and Neurodegenerative Diseases

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