scholarly journals Inhibition of P2X4R attenuates white matter injury in mice after intracerebral hemorrhage by regulating microglial phenotypes

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Xiongjie Fu ◽  
Guoyang Zhou ◽  
Xinyan Wu ◽  
Chaoran Xu ◽  
Hang Zhou ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Crucial Role ◽  
Molecular Mechanisms ◽  
Quantitative Polymerase Chain Reaction ◽  
White Matter Injury ◽  
Western Blots ◽  
Neurobehavioral Function ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

Abstract Background White matter injury (WMI) is a major neuropathological event associated with intracerebral hemorrhage (ICH). P2X purinoreceptor 4 (P2X4R) is a member of the P2X purine receptor family, which plays a crucial role in regulating WMI and neuroinflammation in central nervous system (CNS) diseases. Our study investigated the role of P2X4R in the WMI and the inflammatory response in mice, as well as the possible mechanism of action after ICH. Methods ICH was induced in mice via collagenase injection. Mice were treated with 5-BDBD and ANA-12 to inhibit P2X4R and tropomyosin-related kinase receptor B (TrkB), respectively. Immunostaining and quantitative polymerase chain reaction (qPCR) were performed to detect microglial phenotypes after the inhibition of P2X4R. Western blots (WB) and immunostaining were used to examine WMI and the underlying molecular mechanisms. Cylinder, corner turn, wire hanging, and forelimb placement tests were conducted to evaluate neurobehavioral function. Results After ICH, the protein levels of P2X4R were upregulated, especially on day 7 after ICH, and were mainly located in the microglia. The inhibition of P2X4R via 5-BDBD promoted neurofunctional recovery after ICH as well as the transformation of the pro-inflammatory microglia induced by ICH into an anti-inflammatory phenotype, and attenuated ICH-induced WMI. Furthermore, we found that TrkB blockage can reverse the protective effects of WMI as well as neuroprotection after 5-BDBD treatment. This result indicates that P2X4R plays a crucial role in regulating WMI and neuroinflammation and that P2X4R inhibition may benefit patients with ICH. Conclusions Our results demonstrated that P2X4R contributes to WMI by polarizing microglia into a pro-inflammatory phenotype after ICH. Furthermore, the inhibition of P2X4R promoted pro-inflammatory microglia polarization into an anti-inflammatory phenotype, enhanced brain-derived neurotrophic factor (BDNF) production, and through the BDNF/TrkB pathway, attenuated WMI and improved neurological function. Therefore, the regulation of P2X4R activation may be beneficial for the reducing of ICH-induced brain injury.

scholarly journals Ceria Nanoparticles Ameliorate White Matter Injury After Intracerebral Hemorrhage: Microglia-astrocyte Involvement in Remyelination

2020 ◽  
Author(s):  
Jingwei Zheng ◽  
Jia‘nan Lu ◽  
Shuhao Mei ◽  
Haijian Wu ◽  
Zeyu Sun ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Molecular Mechanisms ◽  
White Matter Injury ◽  
Ceria Nanoparticles ◽  
Ros Scavenging ◽  
Transmission Electron Microscopy Analysis ◽  
Positive Effects ◽  
Myelin Debris

Abstract Background: Intracerebral hemorrhage (ICH) can induce excess accumulation of reactive oxygen species (ROS) and subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration. Methods: ICH was induced in vivo by collagenase VII injection in mice. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocytes alteration and the underlying molecular mechanisms.Results: CeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation at 7 days and 21 days post ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately enhanced in ICH + CeNP + PLX3397 treated mice compared to the ICH + Vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia. Conclusion: The present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.

scholarly journals Ceria nanoparticles ameliorate white matter injury after intracerebral hemorrhage: microglia-astrocyte involvement in remyelination

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Jingwei Zheng ◽  
Jia’nan Lu ◽  
Shuhao Mei ◽  
Haijian Wu ◽  
Zeyu Sun ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Molecular Mechanisms ◽  
White Matter Injury ◽  
Ceria Nanoparticles ◽  
Ros Scavenging ◽  
Transmission Electron Microscopy Analysis ◽  
Positive Effects ◽  
Myelin Debris

Abstract Background Intracerebral hemorrhage (ICH) can induce excessive accumulation of reactive oxygen species (ROS) that may subsequently cause severe white matter injury. The process of oligodendrocyte progenitor cell (OPC) differentiation is orchestrated by microglia and astrocytes, and ROS also drives the activation of microglia and astrocytes. In light of the potent ROS scavenging capacity of ceria nanoparticles (CeNP), we aimed to investigate whether treatment with CeNP ameliorates white matter injury by modulating ROS-induced microglial polarization and astrocyte alteration. Methods ICH was induced in vivo by collagenase VII injection. Mice were administered with PLX3397 for depleting microglia. Primary microglia and astrocytes were used for in vitro experiments. Transmission electron microscopy analysis and immunostaining were performed to verify the positive effects of CeNP in remyelination and OPC differentiation. Flow cytometry, real-time polymerase chain reaction, immunofluorescence and western blotting were used to detect microglia polarization, astrocyte alteration, and the underlying molecular mechanisms. Results CeNP treatment strongly inhibited ROS-induced NF-κB p65 translocation in both microglia and astrocytes, and significantly decreased the expression of M1 microglia and A1 astrocyte. Furthermore, we found that CeNP treatment promoted remyelination and OPC differentiation after ICH, and such effects were alleviated after microglial depletion. Interestingly, we also found that the number of mature oligodendrocytes was moderately increased in ICH + CeNP + PLX3397-treated mice compared to the ICH + vehicle + PLX3397 group. Therefore, astrocytes might participate in the pathophysiological process. The subsequent phagocytosis assay indicated that A1 astrocyte highly expressed C3, which could bind with microglia C3aR and hinder microglial engulfment of myelin debris. This result further replenished the feedback mechanism from astrocytes to microglia. Conclusion The present study reveals a new mechanism in white matter injury after ICH: ICH induces M1 microglia and A1 astrocyte through ROS-induced NF-κB p65 translocation that hinders OPC maturation. Subsequently, A1 astrocytes inhibit microglial phagocytosis of myelin debris via an astrocytic C3-microglial C3aR axis. Polyethylene glycol-CeNP treatment inhibits this pathological process and ultimately promotes remyelination. Such findings enlighten us that astrocytes and microglia should be regarded as a functional unit in future works.

scholarly journals Genomic Profiles of Damage and Protection in Human Intracerebral Hemorrhage

2008 ◽  
Vol 28 (11) ◽  
pp. 1860-1875 ◽  
Author(s):  
S Thomas Carmichael ◽  
Paul M Vespa ◽  
Jeffery L Saver ◽  
Giovanni Coppola ◽  
Daniel H Geschwind ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Transforming Growth Factor Beta ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Apoptotic Cell ◽  
High Rate ◽  
Molecular Networks ◽  
Neuronal Signaling ◽  
Secondary Damage ◽  
Anti Inflammatory

Intracerebral hemorrhage (ICH) produces a high rate of death and disability. The molecular mechanisms of damage in perihematomal tissue in humans have not been systematically characterized. This study determines the gene expression profile and molecular networks that are induced in human perihematomal tissue through molecular analysis of tissue obtained from endoscopic clot evacuation. Differentially expressed genes and their cellular origin were confirmed in a mouse model of ICH. A total of 624 genes showed altered regulation in human ICH. Bioinformatic analysis shows that these genes form interconnected networks of proinflammatory, anti-inflammatory, and neuronal signaling cascades. Intracerebral hemorrhage evokes coordinated upregulation of proinflammatory signaling through specific cytokines and chemokines and their downstream molecular pathways. Anti-inflammatory networks are also induced by ICH, including annexins A1 and A2 and transforming growth factor beta (TGF β) and their intracellular cascades. Intracerebral hemorrhage downregulates many neuronal signaling systems, including the N-methyl-D-aspartic acid (NMDA) receptor complex and membrane ion channels. Select portions of these molecular networks were confirmed in the mouse, and the proteins in a subset of these networks localized to subsets of neurons, oligodendrocytes, or leukocytes. These inflammatory and anti-inflammatory networks interact at several key points in neutrophil signaling, apoptotic cell death, and protease responses, and indicate that secondary damage in ICH activates opposing molecular systems.

scholarly journals Molecular mechanisms underlying anti-inflammatory phenotype of neonatal splenic macrophages

2007 ◽  
Vol 82 (2) ◽  
pp. 403-416 ◽  
Author(s):  
Lakshman Chelvarajan ◽  
Diana Popa ◽  
Yushu Liu ◽  
Thomas V. Getchell ◽  
Arnold J. Stromberg ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Splenic Macrophages ◽  
Inflammatory Phenotype ◽  
Anti Inflammatory

scholarly journals HDAC inhibition reduces white matter injury after intracerebral hemorrhage

2020 ◽  
pp. 0271678X2094261
Author(s):  
Heng Yang ◽  
Wei Ni ◽  
Pengju Wei ◽  
Sicheng Li ◽  
Xinjie Gao ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Hdac Inhibitor ◽  
Histone Deacetylases ◽  
Macrophage Polarization ◽  
Conditional Knockout ◽  
White Matter Injury ◽  
Hdac Inhibition

Inhibition of histone deacetylases (HDACs) has been shown to reduce inflammation and white matter damage after various forms of brain injury via modulation of microglia/macrophage polarization. Previously we showed that the HDAC inhibitor scriptaid could attenuate white matter injury (WMI) after ICH. To access whether modulation of microglia/macrophage polarization might underlie this protection, we investigated the modulatory role of HDAC2 in microglia/macrophage polarization in response to WMI induced by intracerebral hemorrhage (ICH) and in primary microglia and oligodendrocyte co-cultures. HDAC2 activity was inhibited via conditional knockout of the Hdac2 gene in microglia or via administration of scriptaid. Conditional knockout of the Hdac2 gene in microglia and HDAC inhibition with scriptaid both improved neurological functional recovery and reduced WMI after ICH. Additionally, HDAC inhibition shifted microglia/macrophage polarization toward the M2 phenotype and reduced proinflammatory cytokine secretion after ICH in vivo. In vitro, a transwell co-culture model of microglia and oligodendrocytes also demonstrated that the HDAC inhibitor protected oligodendrocytes by modulating microglia polarization and mitigating neuroinflammation. Moreover, we found that scriptaid decreased the expression of pJAK2 and pSTAT1 in cultured microglia when stimulated with hemoglobin. Thus, HDAC inhibition ameliorated ICH-mediated neuroinflammation and WMI by modulating microglia/macrophage polarization.

Taurine supplementation reduces neuroinflammation and protects against white matter injury after intracerebral hemorrhage in rats

Amino Acids ◽  
2017 ◽  
Vol 50 (3-4) ◽  
pp. 439-451 ◽  
Author(s):  
Hengli Zhao ◽  
Jie Qu ◽  
Qiang Li ◽  
Mengchu Cui ◽  
Jie Wang ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
White Matter Injury ◽  
Taurine Supplementation
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