Cysteinyl Leukotriene Receptor 2 is Involved in Inflammation and Neuronal Damage by Mediating Microglia M1/M2 Polarization through NF-κB Pathway

Zhao, Rui; Ying, Miaofa; Gu, Shenglong; Yin, Wei Hsian; Li, Yanwei; Yuan, Hong; Fang, San‐Hua; Li, Mingxing

doi:10.1016/j.neuroscience.2019.10.048

Cited by 79 publications

(39 citation statements)

References 38 publications

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“…Furthermore, localization to general retinal areas, or near to degenerating RGCs may provide information correlating state of activation with effects on retinal degeneration. The correlation between regions of greatest microglial activation with RGC loss in the present study emphasize this elationship, but data do not alllow us to distinguish between microglial activation in response to dying neurons or neurons dying in response to microglial activation; distinguishing between these is of key furure interest.. NF-κB signaling is a well-known effector in the expression of inflammatory cytokines [89][91] [92], and is implicated in polarization to the M1 phenotype [93,94], which was confirmed in our exposure to upstream effector LPS/TLR4 to induce an M1 phenotype (Fig. 3b).…”

Section: P2x7 Receptor Stimulation Results In Mixed Activation Statementioning

confidence: 76%

“…Previous work has indicated that P2X7 stimulation alone can lead to NF-κB translocation to the nucleus via MyD88 [62,95]. Modulation of NF-κB has also been demonstrated to enhance microglial polarization to the M2 phenotype, with has demonstrated benefits in models of spinal cord injury [96] and cerebral ischemic injury [93].…”

Section: P2x7 Receptor Stimulation Results In Mixed Activation Statementioning

confidence: 99%

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Rapid Morphologic and Molecular Activation of Microglial Cells by Stimulation of the P2X7 Receptor Correlates with Neuron Loss

Campagno

Jassim

et al. 2021

Preprint

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Background: The endogenous signals leading to microglial activation represent central components of neuroinflammatory cascades. Given ATP release accompanies mechanical strain to neural tissue, and the P2X7R for ATP is expressed on microglial cells, we examined the morphological and molecular consequences of P2X7R stimulation in vivo and in vitro in detail to enhance understanding of the response. Methods: IL-1β release was determined with ELISA. Expression of mRNA used qPCR. ATP release was determined with the luciferin/luciferase assay while fura-2 indicated cytoplasmic calcium. Microglial migration used Boyden chambers. Morphological changes were quantified from Iba1-immunostained cells. Results: Sholl analysis of Iba1-stained cells showed retraction of microglial ramifications one day after injection of P2X7R agonist BzATP into mouse retinae. Mean branch length also decreased, while cell body size and expression of Nos2, Tnfa, Arg1, Chil3 increased. BzATP induced similar morphological changes in ex vivo tissue isolated from Cx3CR1-GFP mice, suggesting cell recruitment was unnecessary. Primary microglial cultures were developed to investigate the autonomous nature of the response. Isolated microglial cells expressed P2X7R, while increased intracellular Ca 2+ triggered by BzATP and blocked by antagonist A839977 confirmed functional expression. BzATP induced process retraction and cell body enlargement within minutes in isolated microglial cells, and increased expression of Nos2 and Arg1 . BzATP both increased expression of IL-1β, and triggered a substantial release, suggesting P2X7R both primes and activates the NLRP3 inflammasome. ATP increased microglial migration, but this required P2Y12R, not P2X7R involvement. As ATP release often accompanies mechanical strain, responses to intraocular pressure elevation were determined. Transient elevation increased ATP release and led to microglial process retraction, cell body enlargement and gene upregulation resembling the responses to BzATP injection. These pressure-dependent changes to microglia were reduced in P2X7R -/- mice. Critically, the loss of retinal ganglion cell neurons accompanying increased pressure was correlated with microglial activation in C57Bl/6J, but not P2X7R -/- mice.Conclusions: P2X7R stimulation induced morphological and molecular markers of activation in retinal microglial cells in vivo and in vitro , affecting IL-1β release and rapid process retraction but not cell migration. Parallel responses accompanied transient pressure elevation, suggesting ATP release and P2X7R stimulation contribute to the microglial response to rising pressure.

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Section: P2x7 Receptor Stimulation Results In Mixed Activation Statementioning

confidence: 76%

Section: P2x7 Receptor Stimulation Results In Mixed Activation Statementioning

confidence: 99%

Rapid Morphologic and Molecular Activation of Microglial Cells by Stimulation of the P2X7 Receptor Correlates with Neuron Loss

Campagno

Jassim

et al. 2021

Preprint

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“…Our results demonstrated that IH aggravates the brain inflammatory response in patients with T2DM. In the normal central nervous system (CNS), microglia play an important role in maintaining the balance of neuron differentiation and apoptosis by producing neurotrophic proteins (Zhao et al, 2019). There is evidence that several miRNAs are important transcriptional regulators of certain inflammation-related mediators (Marques-Rocha et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Blocking the LncRNA MALAT1/miR-224-5p/NLRP3 Axis Inhibits the Hippocampal Inflammatory Response in T2DM With OSA

Wang

Han

et al. 2020

Front. Cell. Neurosci.

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Studies have shown that diabetes can cause cognitive dysfunction, and cognitive dysfunction in patients with diabetes combined with obstructive sleep apnea (OSA) is more severe. LncRNAs are known to be associated with type 2 diabetes mellitus (T2DM) with OSA. This study aimed to investigate the role and underlying mechanism of the lncRNA MALAT1/miR-224-5p/NLRP3 axis in T2DM with OSA. qRT-PCR was used to quantify the expression of MALAT1, miR-224-5p, and NLRP3 in brain tissues. NLRP3 expression was assessed by immunohistochemistry (IHC) and immunofluorescent labeling. The interaction involving MALAT1, miR-224-5p, and NLRP3 was evaluated by transfection. Western blotting was utilized to evaluate the expression levels of the pathway-related proteins NLRP3, caspase 1, tumor necrosis factor-α (TNF-α) and interleukin-1 β (IL-1β) both in vitro and in vivo. qRT-PCR was used to assess the mRNA expression levels of NLRP3, caspase 1, TNF-α and IL-1β both in vitro and in vivo. In brain tissues of T2DM with OSA, MALAT1 and NLRP3 were overexpressed, while miR-224-5p was downregulated, which was consistent with subsequent cell experiments. We screened the miRNAs that could bind to MALAT1 and NLRP3 by the StarBase database and the TargetScanMouse7.2 website. Our research showed that among these miRNAs, the level of miR-224-5p was most significantly negatively correlated with the levels of MALAT1 and NLRP3. Also, a firefly luciferase assay showed that miR-224-5p, which is a target of MALAT1, directly reduced the expression of the downstream protein NLRP3. Overexpression of miR-224-5p significantly inhibited the expression levels of NLRP3, caspase 1, TNF-α and IL-1β in vitro. MALAT1 promoted NLRP3 expression by acting as a competing endogenous RNA and sponging miR-224-5p. MiR-224-5p reduces microglial inflammation activation through the regulation of NLRP3 expression, which ultimately affected the NLRP3/IL-1β pathway in the hippocampus. This suggests that miR-224-5p may serve as a potential target for T2DM and OSA therapy.

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“…These findings suggest that RIPK1 plays a role in mediating the secretion of inflammatory factors in M1 phenotypic microglia after OGD. RhTrx‐1 therapy inhibits the expression of microglial RIPK1 and regulates the expression of M1/M2 phenotype of microglia, which ultimately plays a neuroprotective role 45,46 . Besides, inhibition of inflammation during ischaemic stroke contributes to reduce ischaemic infarction 24,30,41 .…”

Section: Discussionmentioning

confidence: 99%

“…RhTrx-1 therapy inhibits the expression of microglial RIPK1 and regulates the expression of M1/M2 phenotype of microglia, which ultimately plays a neuroprotective role. 45,46 Besides, inhibition of inflammation during ischaemic stroke contributes to reduce ischaemic infarction. 24,30,41 Based on this evidence, we further in- 20 Ma et al demonstrated that rhTrx-1 exerts an antioxidative effect against neurological dysfunction and cerebral infarction.…”

Section: F I G U R Ementioning

confidence: 99%

Inhibition of microglial receptor‐interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke

Jiao

Wang

Zhang

et al. 2020

J Cellular Molecular Medi

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Cysteinyl Leukotriene Receptor 2 is Involved in Inflammation and Neuronal Damage by Mediating Microglia M1/M2 Polarization through NF-κB Pathway

Cited by 79 publications

References 38 publications

Rapid Morphologic and Molecular Activation of Microglial Cells by Stimulation of the P2X7 Receptor Correlates with Neuron Loss

Rapid Morphologic and Molecular Activation of Microglial Cells by Stimulation of the P2X7 Receptor Correlates with Neuron Loss

Blocking the LncRNA MALAT1/miR-224-5p/NLRP3 Axis Inhibits the Hippocampal Inflammatory Response in T2DM With OSA

Inhibition of microglial receptor‐interacting protein kinase 1 ameliorates neuroinflammation following cerebral ischaemic stroke

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