Transcriptional Regulation of Microglial Metabolic and Activation States by P2RY12
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ABSTRACT:
PROVIDER: PRJNA1259521 | ENA |
REPOSITORIES: ENA
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Project description:Microglia are the resident immune cells of the CNS and integral to maintaining homeostasis. They rapidly respond to injury or infection within the CNS by altering their morphology, proliferating, and releasing cytokines and other signaling molecules. Microglia also play critical roles in development, regulating synaptic pruning and debris clearance. In disease, they are powerful mediators of neuroinflammation. Understanding the molecular pathways involved in microglial function is pivotal for advancing neurobiological research and developing effective strategies for CNS disorders. In this context, P2RY12 is a G protein-coupled receptor (GPCR) that is enriched in microglia in the brain parenchyma and is part of the transcriptional signature of homeostatic, ramified microglia. However, P2RY12 is downregulated in activated microglia and in neurological conditions. The downstream effects of P2RY12 downregulation in disease-associated microglia and how they influence microglial activation remain inadequately understood. In this study, we apply transcriptional and histological methods to explore the changes to microglia upon a genetic P2RY12 loss. Our findings reveal that P2RY12-deficient microglia experience alterations in distinct metabolic pathways while preserving overall homeostatic microglial transcriptional identity. P2RY12 deficiency dysregulates signature genes involved in homeostatic iron metabolism. Importantly, the Glutathione Peroxidase 4 (GPX4)-Glutathione (GSH) antioxidant pathway related to ferroptosis susceptibility is impaired upon microglial activation with LPS treatment. These results highlight the critical role of P2RY12 in regulating microglial immune and metabolic responses under both homeostatic and inflammatory conditions, providing insights into its involvement in CNS pathophysiology.
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Project description:Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α, and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway. Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically, co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore, phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.
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Project description:Microglial overactivation is actively involved in the pathogenesis of neurodegenerative diseases. Polo-like kinase 2 (PLK2) is a serine/threonine protein kinase associated with the regulation of synaptic plasticity and centriole duplication. Here, we identified PLK2 as an important early response gene in lipopolysaccharide (LPS)-stimulated microglial cells. Knockdown or inhibition of PLK2 remarkably attenuated LPS-induced expression of pro-inflammatory factors such as IL-1β, IL-6, COX2, TNF-α,and iNOS in microglial cells via suppressing the IKKβ-NF-κB signaling pathway.Notably, overexpression of PLK2 induced expression of pro-inflammatory factors and NF-κB transcriptional activation in the absence of inflammatory stimuli. Mechanistically,co-immunoprecipitation experiments revealed association between PLK2 and IKKβ, whereas GST pull-down assay showed no direct interaction between PLK2 and IKKβ. Proteomic analysis and in vitro kinase assay identified heat shock protein 90 alpha (HSP90α), a regulator of IKKβ activity, as a novel PLK2 substrate. Knockdown or pharmacological inhibition of HSP90α abolished PLK2-mediated activation of NF-κB transcriptional activity and microglial inflammatory activation. Furthermore,phosphoproteomic analysis pinpointed Ser252 and Ser263 on HSP90α as novel phosphorylation targets of PLK2. Subsequent functional studies demonstrated that re-expression of phosphor-dead mutation of these two phosphorylation sites on HSP90α failed to rescue the PLK2-induced activation of the NF-κB signaling. Lastly, conditional knockout of PLK2 in microglial cells dramatically ameliorated neuroinflammation and subsequent dopaminergic neuron loss in an intracranial LPS-induced mouse PD model. The present study revealed, for the first time, that PLK2 promoted microglial activation through the phosphorylation of HSP90α and subsequent activation of the IKKβ-NF-κB signaling pathway. Consequently, PLK2 emerges as a potential therapeutic target for the amelioration of neuroinflammation-related diseases.
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Project description:Microglia are phagocytic cells that survey the brain and perform neuroprotective functions in response to tissue damage, but their activating receptors are largely unknown. Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial immunoreceptor whose loss-of-function mutations in humans cause presenile dementia, while genetic variants are associated with increased risk of neurodegenerative diseases. In myeloid cells, TREM2 has been involved in the regulation of phagocytosis, cell proliferation and inflammatory responses in vitro. However, it is unknown how TREM2 contributes to microglia function in vivo. Here, we identify a critical role for TREM2 in the activation and function of microglia during cuprizone (CPZ)-induced demyelination. TREM2-deficient (TREM2(-/-)) mice had defective clearance of myelin debris and more axonal pathology, resulting in impaired clinical performances compared to wild-type (WT) mice. TREM2(-/-) microglia proliferated less in areas of demyelination and were less activated, displaying a more resting morphology and decreased expression of the activation markers MHC II and inducible nitric oxide synthase as compared to WT. Mechanistically, gene expression and ultrastructural analysis of microglia suggested a defect in myelin degradation and phagosome processing during CPZ intoxication in TREM2(-/-) microglia. These findings place TREM2 as a key regulator of microglia activation in vivo in response to tissue damage. Two STAGE (6weeks 12 weeks),
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Project description:Polo like kinase 2 (PLK2) promotes microglial activation via regulation of the HSP90α/IKKβ pathway
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