The Dynamics of Microglial Polarization Reveal the Resident Neuroinflammatory Responses After Subarachnoid Hemorrhage

Zheng, Zhenlong; Lyu, Hao; Lam, Sin Yu Erica; Lam, P. M.; Poon, Wai Sang; Wong, George Kwok Chu

doi:10.1007/s12975-019-00728-5

Cited by 90 publications

(90 citation statements)

References 43 publications

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“…They are the first and most important line of defense against CNS insults [6]. After SAH, a large number of microglia are activated and release inflammatory factors, which would lead to inflammatory responses and aggravate the neurological deficit [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

CX3CL1/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage

Chen

Jiang

et al. 2020

J Neuroinflammation

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Background: Microglial activation-mediated neuroinflammation is a major contributor to early brain injury (EBI) after subarachnoid hemorrhage (SAH). MicroRNA-124 (miR-124) is the most abundant miRNAs in the central nervous system (CNS) and plays a vital role in microglial activation by targeting protein CCAAT-enhancer-binding protein α (C/EBPα). It has been reported that the CX3CL1/CX3CR1 axis is involved in the delivery of miR-124 from neurons to microglia. Methods: An experimental rat SAH model was established by injecting autologous arterial blood into the prechiasmatic cistern, and cultured primary neurons and microglia were exposed to oxyhemoglobin to mimic SAH in vitro. We additionally exploited specific expression plasmids encoding CX3CL1 and CX3CR1. Results: We observed significant decreases in CX3CL1 and CX3CR1 in the brain tissues of SAH patients. We also observed decreases in the levels of CX3CL1 in neurons and CX3CR1 in microglia after SAH in rats. Moreover, microglia exhibited an activated phenotype with macrophage-like morphology and high levels of CD45 and major histocompatibility complex (MHC) class II after SAH. After overexpression of CX3CL1/CX3CR1, the level of CD45 and MHC class II and the release of inflammatory factors tumor necrosis factor α, interleukin 1α and complement 1q were significantly decreased. There was also increased neuronal degeneration and behavior dysfunction after SAH, both of which were inhibited by CX3CL1/CX3CR1 overexpression. Additionally, we found that the delivery of exosomal miR-124 from neurons to microglia was significantly reduced after SAH, accompanied by an increase in C/EBPα expression, and was inhibited by CX3CL1/CX3CR1 overexpression. In conclusion, the CX3CL1/CX3CR1 axis may play protective roles after SAH by promoting the delivery of exosomal miR-124 to microglia and attenuate microglial activation and neuroinflammation. Conclusions: CX3CL1/CX3CR1 axis may be a potential intervention target for the inhibition of SAH-induced EBI by promoting exosome transport of miR-124 to microglia.

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Section: Introductionmentioning

confidence: 99%

CX3CL1/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage

Chen

Jiang

et al. 2020

J Neuroinflammation

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“…TGF-β, as an anti-inflammatory cytokine, is associated with tissue repair. We next investigated the effect of rhFGF21 on inflammatory gene (TNF-α, IL-1β, IL-6, TGF-β) expression in microglia and invading peripheral macrophages, which are defined as the major cellular contributors to neuroinflammation [44,45]. Although there are analogous phenotypic and functional characteristics among these inflammatory genes, numerous studies have revealed that they may play unique roles under pathological condition [46].…”

Section: Discussionmentioning

confidence: 99%

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

Wang

Liu

Zhu

et al. 2020

Preprint

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Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion：In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment. Keywords : rhFGF21, stroke, neuroinflammation, microglia/macrophage, NF-κB, PPAR-γ

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“…TGF-β, as an anti-in ammatory cytokine, is associated with tissue repair. We next investigated the effect of rhFGF21 on in ammatory gene (TNF-α, IL-1β, IL-6, TGF-β) expression in microglia and invading peripheral macrophages, which are de ned as the major cellular contributors to neuroin ammation [46,47]. Although there are analogous phenotypic and functional characteristics among these in ammatory genes, numerous studies have revealed that they may play unique roles under pathological conditions [48].…”

Section: Discussionmentioning

confidence: 99%

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

Wang

Liu

Zhu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Resident microglia and macrophages are the predominant contributors to neuroinflammation and immune reactions, which play a critical role in the pathogenesis of ischemic brain injury. Controlling inflammatory responses is considered a promising therapeutic approach for stroke. Recombinant human fibroblast growth factor 21 (rhFGF21) has anti-inflammatory properties by modulating microglia and macrophages, but our knowledge of the inflammatory modulation of rhFGF21 in focal cerebral ischemia is lacking. Therefore, we investigated whether rhFGF21 improves ischemic outcomes in experimental stroke by targeting microglia and macrophages. Methods: C57BL/6 mice were subjected to transient middle cerebral artery occlusion (tMCAO) and randomly divided into groups that received intraperitoneal rhFGF21 or vehicle daily starting at 6 h after reperfusion. Behavior assessments were monitored for 14 d after tMACO and the gene expression levels of inflammatory cytokines were analyzed with qPCR. The phenotypic variation of microglia/macrophages and the presence of infiltrated immune cells were examined by flow cytometry and immunostaining. Additionally, magnetic cell sorting (MACS) in combination with fluorescence-activated cell sorting (FACS) was used to purify microglia and macrophages. Results: rhFGF21 administration ameliorated neurological deficits in behavioral tests by regulating the secretion of pro-inflammatory and anti-inflammatory cytokines. rhFGF21 also attenuated the polarization of microglia/macrophages toward the M1 phenotype and the accumulation of peripheral immune cells after stroke, accompanied by a temporal evolution of the phenotype of microglia/macrophages and infiltration of peripheral immune cells. Furthermore, rhFGF21 treatment through its actions on FGF receptor 1(FGFR1) inhibited M1 polarization of microglia and pro-inflammatory cytokine expression by suppressing nuclear factor-kappa B (NF-κB ) and upregulating peroxisome proliferator-activated receptor PPAR-γ. conclusion： In summary, rhFGF21 treatment promoted functional recovery in experimental stroke by modulating microglia/macrophage-mediated neuroinflammation via the NF-κB and PPAR-γ signaling pathways, making it a potential anti-inflammatory agent for stroke treatment.

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The Dynamics of Microglial Polarization Reveal the Resident Neuroinflammatory Responses After Subarachnoid Hemorrhage

Cited by 90 publications

References 43 publications

CX3CL1/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage

CX3CL1/CX3CR1 axis attenuates early brain injury via promoting the delivery of exosomal microRNA-124 from neuron to microglia after subarachnoid hemorrhage

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

FGF21 alleviates neuroinflammation following ischemic stroke by modulating the temporal and spatial dynamics of microglia/macrophages

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