Mesencephalic astrocyte‐derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage
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            activating Akt‐dependent prosurvival pathway and defending blood‐brain barrier integrity

Li, Tao; Xu, Weilin; Gao, Liansheng; Guan, Guo-ping; Zhang, Zhongyuan; He, Pingyou; Xu, Hangzhe; Fan, Linfeng; Yan, Feng; Chen, Gao

doi:10.1096/fj.201800227rr

Cited by 37 publications

(39 citation statements)

References 58 publications

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“…In earlier studies, MANF was shown to be induced at the early stage of brain ischemia, decreasing to the control level at 1 wk after ischemia[ 17 , 46 ]. The protein levels of MANF started to increase at 3 h, and peaked at 24 h in a rat model of intracerebral or subarachnoid hemorrhage[ 47 , 48 ]. These results indicated that MANF was induced by ER stress in a time-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Yang¹,

Li²,

Qu³

et al. 2020

WJSC

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BACKGROUND Bone marrow mesenchymal stem cells (BMSCs) are capable of shifting the microglia/macrophages phenotype from M1 to M2, contributing to BMSCs-induced brain repair. However, the regulatory mechanism of BMSCs on microglia/macrophages after ischemic stroke is unclear. Recent evidence suggests that mesencephalic astrocyte–derived neurotrophic factor (MANF) and platelet-derived growth factor-AA (PDGF-AA)/MANF signaling regulate M1/M2 macrophage polarization. AIM To investigate whether and how MANF or PDGF-AA/MANF signaling influences BMSCs-mediated M2 polarization. METHODS We identified the secretion of MANF by BMSCs and developed transgenic BMSCs using a targeting small interfering RNA for knockdown of MANF expression. Using a rat middle cerebral artery occlusion (MCAO) model transplanted by BMSCs and BMSCs–microglia Transwell coculture system, the effect of BMSCs-induced downregulation of MANF expression on the phenotype of microglia/macrophages was tested by Western blot, quantitative reverse transcription-polymerase chain reaction, and immunofluorescence. Additionally, microglia were transfected with mimics of miR-30a*, which inﬂuenced expression of X-box binding protein (XBP) 1, a key transcription factor that synergized with activating transcription factor 6 (ATF6) to govern MANF expression. We examined the levels of miR-30a*, ATF6, XBP1, and MANF after PDGF-AA treatment in the activated microglia. RESULTS Inhibition of MANF attenuated BMSCs-induced functional recovery and decreased M2 marker production, but increased M1 marker expression in vivo or in vitro . Furthermore, PDGF-AA treatment decreased miR-30a* expression, had no influence on the levels of ATF6, but enhanced expression of both XBP1 and MANF. CONCLUSION BMSCs-mediated MANF paracrine signaling, in particular the PDGF-AA/miR-30a*/XBP1/MANF pathway, synergistically mediates BMSCs-induced M2 polarization.

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Section: Discussionmentioning

confidence: 99%

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Yang¹,

Li²,

Qu³

et al. 2020

WJSC

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“…In an in vitro study, extracellular MANF was shown to protect human neuroblastoma SH-SY5Y cells from 6-hydroxydopamine (6-OHDA) induced cell death via the activation of PI3K/Akt/mTOR pathway (Hao et al, 2017). In addition to mTOR, several other downstream effectors of the PI3K/Akt signaling pathway including GSK3β, MDM2, and NF-κB have been reported to be activated by treatment of recombinant hMANF in the rodent brain, which was associated with enhanced neuron survival in neurodegenerative diseases and intracerebral hemorrhage models (Hao et al, 2017;Zhang et al, 2017b;Li et al, 2018;Xu M. et al, 2018). MANF has also been reported to activate Erk in a study showing that intracellular MANF overexpression facilitated neuron migration and activated STAT3 and Erk in mice SVZ explant (Tseng et al, 2017a).…”

Section: Discussionmentioning

confidence: 99%

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Wen

Wang

et al. 2020

Front. Mol. Neurosci.

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Neurite outgrowth is essential for brain development and the recovery of brain injury and neurodegenerative diseases. In this study, we examined the role of the neurotrophic factor MANF in regulating neurite outgrowth. We generated MANF knockout (KO) neuro2a (N2a) cell lines using clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9 and demonstrated that MANF KO N2a cells failed to grow neurites in response to RA stimulation. Using MANF siRNA, this finding was confirmed in human SH-SY5Y neuronal cell line. Nevertheless, MANF overexpression by adenovirus transduction or addition of MANF into culture media facilitated the growth of longer neurites in RA-treated N2a cells. MANF deficiency resulted in inhibition of Akt, Erk, mTOR, and P70S6, and impaired protein synthesis. MANF overexpression on the other hand facilitated the growth of longer neurites by activating Akt, Erk, mTOR, and P70S6. Pharmacological blockade of Akt, Erk or mTOR eliminated the promoting effect of MANF on neurite outgrowth. These findings suggest that MANF positively regulated neurite outgrowth by activating Akt/mTOR and Erk/mTOR signaling pathways.

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“…Western blotting was conducted as previously described [31]. Proteins from brain samples and cultured BV2 cells were lysed using RIPA lysis buffer.…”

Section: Western Blottingmentioning

confidence: 99%

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

Peng

Zhuang

Ying

et al. 2020

J Neuroinflammation

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Background: Neuroinflammation is closely associated with the poor prognosis in subarachnoid hemorrhage (SAH) patients. This study was aimed to determine the role of stimulator of IFN genes (STING), an essential regulator to innate immunity, in the context of SAH. Methods: A total of 344 male C57BL/6 J mice were subjected to endovascular perforation to develop a model of SAH. Selective STING antagonist C-176 and STING agonist CMA were administered at 30 min or 1 h post-modeling separately. To investigate the underlying mechanism, the AMPK inhibitor compound C was administered intracerebroventricularly at 30 min before surgery. Post-SAH assessments included SAH grade, neurological test, brain water content, western blotting, RT-PCR, and immunofluorescence. Oxygenated hemoglobin was introduced into BV2 cells to establish a SAH model in vitro. Results: STING was mainly distributed in microglia, and microglial STING expression was significantly increased after SAH. Administration of C-176 substantially attenuated SAH-induced brain edema and neuronal injury. More importantly, C-176 significantly alleviated both short-term and persistent neurological dysfunction after SAH. Meanwhile, STING agonist CMA remarkably exacerbated neuronal injury and deteriorated neurological impairments. Mechanically, STING activation aggravated neuroinflammation via promoting microglial activation and polarizing into M1 phenotype, evidenced by microglial morphological changes, as well as the increased level of microglial M1 markers including IL-1β, iNOS, IL-6, TNF-α, MCP-1, and NLRP3 inflammasome, while C-176 conferred a robust antiinflammatory effect. However, all the mentioned beneficial effects of C-176 including alleviated neuroinflammation, attenuated neuronal injury and the improved neurological function were reversed by AMPK inhibitor compound C. Meanwhile, the critical role of AMPK signal in C-176 mediated anti-inflammatory effect was also confirmed in vitro.

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Mesencephalic astrocyte‐derived neurotrophic factor affords neuroprotection to early brain injury induced by subarachnoid hemorrhage via activating Akt‐dependent prosurvival pathway and defending blood‐brain barrier integrity

Cited by 37 publications

References 58 publications

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Bone marrow mesenchymal stem cells induce M2 microglia polarization through PDGF-AA/MANF signaling

Mesencephalic Astrocyte-Derived Neurotrophic Factor (MANF) Regulates Neurite Outgrowth Through the Activation of Akt/mTOR and Erk/mTOR Signaling Pathways

Stimulator of IFN genes mediates neuroinflammatory injury by suppressing AMPK signal in experimental subarachnoid hemorrhage

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