MFG‐E8 reverses microglial‐induced neurotoxic astrocyte (A1) via NF‐κB and PI3K‐Akt pathways

Xu, Xiequn; Zhang, Aiwu; Zhu, Yingting; He, Wen; Di, Wei; Yu, Fang; Shi, Xiaolei

doi:10.1002/jcp.26918

Cited by 143 publications

(93 citation statements)

References 35 publications

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“…As well as releasing a potent neurotoxin, A1 astrocytes were less able to promote the formation of new synapses, and caused a decrease in the excitatory function of CNS neurons 35 . Recently more and more researches indicate that A1 astrocytes may encourage the development of neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis (MS), and block of A1 astrocyte conversion by microglia is neuroprotective 35,[69][70][71] . The A2 astrocyte-related gene S100A10 is essential for cell proliferation, membrane repair, and inhibition of cell apoptosis 35 .…”

Section: Discussionmentioning

confidence: 99%

Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway

et al. 2020

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Spinal cord injury (SCI) is a severe neurological disease; however, there is no effective treatment for spinal cord injury. Neuroinflammation involves the activation of resident microglia and the infiltration of macrophages is the major pathogenesis of SCI secondary injury and considered to be the therapeutic target of SCI. Parthenolide (PN) has been reported to exert anti-inflammatory effects in fever, migraines, arthritis, and superficial inflammation; however, the role of PN in SCI therapeutics has not been clarified. In this study, we showed that PN could improve the functional recovery of spinal cord in mice as revealed by increased BMS scores and decreased cavity of spinal cord injury in vivo. Immunofluorescence staining experiments confirmed that PN could promote axonal regeneration, increase myelin reconstitution, reduce chondroitin sulfate formation, inhibit scar hyperplasia, suppress the activation of A1 neurotoxic reactive astrocytes and facilitate shift from M1 to M2 polarization of microglia/macrophages. To verify how PN exerts its effects on microglia/macrophages polarization, we performed the mechanism study in vitro in microglia cell line BV-2. PN could significantly reduce M1 polarization in BV2 cells and partially rescue the decrease in the expression of M2 phenotype markers of microglia/macrophage induced by LPS, but no significant effect on M2 polarization stimulated with IL-4 was observed. Further study demonstrated PN inhibited NF-κB signal pathway directly or indirectly, and suppressed activation of signal transducer and activator of transcription 1 or 3 (STAT1/3) via reducing the expression of HDAC1 and subsequently increasing the levels of STAT1/3 acetylation. Overall, our study illustrated that PN may be a promising strategy for traumatic SCI.

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Section: Discussionmentioning

confidence: 99%

Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway

et al. 2020

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“…Recent studies have shown that amyloid-β (Aβ) directly activated astrocytic NF-κB and C3 release, consistent with the high expression of C3 seen in patients with Alzheimer's disease (32). Moreover, the Aβ-activated microglia CM also induced A1 harmful astrocytes via the NF-κB signaling pathway (27). In addition, ROS is known to be implicated in driving astrocyte reactivity and regulating NF-κB activation (20,21).…”

Section: Discussionmentioning

confidence: 80%

“…Afterward, the supernatant containing microglia was obtained and re-plated on PDL-coated T-asks. For the astrocyte culture, the ask with mixed glial cultures was shaken for another 3 h at 250 rpm to remove OPCs, and then puri ed astrocytes were obtained (27,28).…”

Section: Primary Microglia and Astrocyte Culture And Treatmentmentioning

confidence: 99%

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

Zheng¹,

Lu²,

Mei³

et al. 2020

Preprint

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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.

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“…Two proteins, MFG-E8 and SPARC, are down-regulated in the presence of Rapa at 48 hpt (Table 2). These proteins have been associated with astrocyte-synapse and astrocyte-endothelial cell interactions and in the suppression of A1 reactive astrocytes via the up-regulation of PI3K-Akt and the down-regulation of nuclear factor-κB pathways [34,35]. MFG-E8 also has a protective role against Alzheimer's Disease by upregulating the induction of neurogenesis and neural stem cell proliferation [36].…”

Section: Implications Of Bafa1/rapa-dysregulated Intracellular Astrocmentioning

confidence: 99%

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

Sher

Gao

Coombs

2020

Cells

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Autophagy is a key cellular process that involves constituent degradation and recycling during cellular development and homeostasis. Autophagy also plays key roles in antimicrobial host defense and numerous pathogenic organisms have developed strategies to take advantage of and/or modulate cellular autophagy. Several pharmacologic compounds, such as BafilomycinA1, an autophagy inducer, and Rapamycin, an autophagy inhibitor, have been used to modulate autophagy, and their effects upon notable autophagy markers, such as LC3 protein lipidation and Sequestosome-1/p62 alterations are well defined. We sought to understand whether such autophagy modulators have a more global effect upon host cells and used a recently developed aptamer-based proteomic platform (SOMAscan®) to examine 1305 U-251 astrocytic cell proteins after the cells were treated with each compound. These analyses, and complementary cytokine array analyses of culture supernatants after drug treatment, revealed substantial perturbations in the U-251 astrocyte cellular proteome. Several proteins, including cathepsins, which have a role in autophagy, were differentially dysregulated by the two drugs as might be expected. Many proteins, not previously known to be involved in autophagy, were significantly dysregulated by the compounds, and several, including lactadherin and granulins, were up-regulated by both drugs. These data indicate that these two compounds, routinely used to help dissect cellular autophagy, have much more profound effects upon cellular proteins.

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MFG‐E8 reverses microglial‐induced neurotoxic astrocyte (A1) via NF‐κB and PI3K‐Akt pathways

Cited by 143 publications

References 35 publications

Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway

Parthenolide promotes the repair of spinal cord injury by modulating M1/M2 polarization via the NF-κB and STAT 1/3 signaling pathway

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

Autophagy Modulators Profoundly Alter the Astrocyte Cellular Proteome

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