Downregulation of lncRNA KCNQ1OT1 relieves traumatic brain injury induced neurological deficits via promoting "M2" microglia polarization

Liu, Na; Sun, Hanjun; Li, Xuezhong; Cao, Wei; Peng, Aini; Dong, Su-Yan; Yu, Zhixin

doi:10.1016/j.brainresbull.2021.03.004

Cited by 30 publications

(17 citation statements)

References 39 publications

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“…Liu et al showed that KCNQ1OT1 was markedly overexpressed in the cerebral tissue of TBI mice, and knockdown of KCNQ1OT1 in the mouse brain exhibited alleviated neurological deficits, neuronal loss, microglial activation, pro-inflammatory cytokines expression (e.g., IL-1β, TNF-α, IL-6, etc. ), and augmented anti-inflammatory cytokines (e.g., IL-10, transforming growth factor β (TGFβ), brain-derived neurotrophic factor (BDNF)) accompanied by improved BBB integrity and functions [ 120 ]. Authors also confirmed that miR-873-5p was a direct target of KCNQ1OT1, which functioned as a competitive endogenous RNA to sponge miR-873-5p, thus knocking down the levels of KCNQ1OT1 in the brain effectively decreased the levels of tumor necrosis factor receptor-related factor 6 (TRAF6) [ 120 ].…”

Section: Non-coding Rnas Regulate Bbb/bscb Functions In Cns Disordersmentioning

confidence: 99%

Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders

Sun

Hamblin

Yin

2022

Fluids Barriers CNS

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The blood–brain barrier (BBB) is an essential component of the neurovascular unit that controls the exchanges of various biological substances between the blood and the brain. BBB damage is a common feature of different central nervous systems (CNS) disorders and plays a vital role in the pathogenesis of the diseases. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNA (lncRNAs), and circular RNAs (circRNAs), are important regulatory RNA molecules that are involved in almost all cellular processes in normal development and various diseases, including CNS diseases. Cumulative evidences have demonstrated ncRNA regulation of BBB functions in different CNS diseases. In this review, we have summarized the miRNAs, lncRNAs, and circRNAs that can be served as diagnostic and prognostic biomarkers for BBB injuries, and demonstrated the involvement and underlying mechanisms of ncRNAs in modulating BBB structure and function in various CNS diseases, including ischemic stroke, hemorrhagic stroke, traumatic brain injury (TBI), spinal cord injury (SCI), multiple sclerosis (MS), Alzheimer's disease (AD), vascular cognitive impairment and dementia (VCID), brain tumors, brain infections, diabetes, sepsis-associated encephalopathy (SAE), and others. We have also discussed the pharmaceutical drugs that can regulate BBB functions via ncRNAs-related signaling cascades in CNS disorders, along with the challenges, perspective, and therapeutic potential of ncRNA regulation of BBB functions in CNS diseases.

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Section: Non-coding Rnas Regulate Bbb/bscb Functions In Cns Disordersmentioning

confidence: 99%

Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders

Sun

Hamblin

Yin

2022

Fluids Barriers CNS

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“…In this review, the lncRNA/circRNA-miRNA-mRNA regulatory network also exists in microglia and astrocyte mediated neurological diseases, including SCI (Figure 1; Shao et al, 2020; FIGURE 1 | The lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte regulated neurological diseases. Xu S. et al, 2020;Zhao Q. et al, 2020;Cui et al, 2021;Xiang et al, 2021;Chen et al, 2022), TBI (He et al, 2021;Liu N. et al, 2021;Meng et al, 2021), cerebral IRI (Figure 1; Wang et al, 2020c;Yang et al, 2021), stroke (Figure 1; Qi et al, 2017;Han B. et al, 2018;Tian et al, 2021;Zhang M. et al, 2021), epilepsy (Figure 1; Feng et al, 2020;Han C. L. et al, 2020;Wan and Yang, 2020;Xiaoying et al, 2020), neuropathic pain (Figure 1; Chen M. et al, 2020), PD (Figure 1; Cao et al, 2018Cao et al, , 2021, and depression (Figure 1; . We also found that some therapies can impair the ncRNA-glial cell axis and thus inhibit disease development.…”

Section: Discussionmentioning

confidence: 99%

“…KCNQ1OT1 down-regulation can increase miR-873-5p expression. Reducing KCNQ1OT1 blocks microglial inflammation through the miR-873-5p-TRAF6 axis (Liu N. et al, 2021). Liu N. et al (2021) revealed that KCNQ1OT1 depletion can mitigate TBI-induced injuries, including neurological deficits, neuron loss, brain edema, and blood-brain barrier damage (Liu N. et al, 2021).…”

Section: Traumatic Brain Injurymentioning

confidence: 99%

“…Reducing KCNQ1OT1 blocks microglial inflammation through the miR-873-5p-TRAF6 axis (Liu N. et al, 2021). Liu N. et al (2021) revealed that KCNQ1OT1 depletion can mitigate TBI-induced injuries, including neurological deficits, neuron loss, brain edema, and blood-brain barrier damage (Liu N. et al, 2021). Many studies revealed that inhibiting microglial activation and neuroinflammation can hamper TBI development (Kumar et al, 2017).…”

Section: Traumatic Brain Injurymentioning

confidence: 99%

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Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Chen

Lai

Wang

et al. 2021

Front. Mol. Neurosci.

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Microglia and astrocytes maintain tissue homeostasis in the nervous system. Both microglia and astrocytes have pro-inflammatory phenotype and anti-inflammatory phenotype. Activated microglia and activated astrocytes can contribute to several neurological diseases. Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs), two groups of non-coding RNAs (ncRNAs), can function as competing endogenous RNAs (ceRNAs) to impair the microRNA (miRNA) inhibition on targeted messenger RNAs (mRNAs). LncRNAs and circRNAs are involved in various neurological disorders. In this review, we summarized that lncRNAs and circRNAs participate in microglia dysfunction, astrocyte dysfunction, neuron damage, and inflammation. Thereby, lncRNAs and circRNAs can positively or negatively regulate neurological diseases, including spinal cord injury (SCI), traumatic brain injury (TBI), ischemia-reperfusion injury (IRI), stroke, neuropathic pain, epilepsy, Parkinson’s disease (PD), multiple sclerosis (MS), and Alzheimer’s disease (AD). Besides, we also found a lncRNA/circRNA-miRNA-mRNA regulatory network in microglia and astrocyte mediated neurological diseases. Through this review, we hope to cast light on the regulatory mechanisms of lncRNAs and circRNAs in microglia and astrocyte mediated neurological diseases and provide new insights for neurological disease treatment.

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“…Activating the peroxisome proliferator–activated receptor-gamma (PPARγ) by rosiglitazone improved the neurological function and axonal injury via transforming the “M2” polarization of microglia ( Wen et al, 2018 ; Liu et al, 2016 ). Thus, it is conceivable to modulate the formation of M1/M2 microglia, thereby reducing further inflammatory damage from taking place ( Ni et al, 2019 ; Liu et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization

Jiang

Ding

et al. 2021

Front. Pharmacol.

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Background: Phillyrin (Phi) is the main polyphenolic compound found in Forsythia suspensa. Recent studies have revealed that Phi has potent antioxidative and anti-inflammatory effects. However, whether Phi could relieve blood–brain barrier (BBB) damage following traumatic brain injury (TBI) remains unknown.Materials and Methods: Lipopolysaccharide (LPS) was used to activate primary microglia, which were then treated with different doses of Phi or the peroxisome proliferator–activated receptor-gamma (PPARγ) antagonist (GW9662). CCK-8 assay was used for evaluating cell viability, and the cytokines (including IL-1β, IL-6, TNFα, IL-4, IL-10, and TGFβ), microglial phenotypic markers (iNOS, COX2, and CD86 for “M1” polarization; Arg1, Ym1, and CD206 for “M2” polarization), PPARγ, and NF-κB were determined by RT-PCR, Western blot, or cellular immunofluorescence. Primary cultured mouse brain microvascular endothelial cells (BMECs) were stimulated by the condition medium (CM) from microglia. The cell viability, angiogenesis, and tight junction of BMECs were determined via CCK-8 assay, tube formation assay, and Western blot (for detecting MMP3, MMP9, ZO1, claudin-5, and occludin). Furthermore, the mouse TBI model was constructed and treated with Phi and/or GW9662. The BBB integrity was evaluated by H&E staining, Evans blue staining, and tissue immunofluorescence.Results: Phi markedly restrained the pro-inflammatory (“M1” state) cytokines and promoted anti-inflammatory (“M2” polarization) cytokines in LPS-mediated microglia. Phi mitigated “M1” polarization and promoted “M2” polarization of microglia via enhancing PPARγ and inhibiting the NF-κB pathway. The PPARγ antagonist GW9662 significantly repressed Phi-mediated anti-inflammatory effects. Meanwhile, Phi enhanced the viability, tube formation ability, and cell junction of BMECs. In the TBI mouse model, Phi promoted “M2” polarization, whereas it repressed the “M1” polarization of microglia. In addition, Phi reduced TBI-mediated BBB damage. However, the protective effects of Phi were reversed mainly by GW9662 treatment.Conclusion: Phi prevents BBB damage via inhibiting the neuroinflammation of microglia through the PPARγ/NF-κB pathway, which provides a potential therapeutic drug against TBI.

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Downregulation of lncRNA KCNQ1OT1 relieves traumatic brain injury induced neurological deficits via promoting "M2" microglia polarization

Cited by 30 publications

References 39 publications

Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders

Non-coding RNAs in the regulation of blood–brain barrier functions in central nervous system disorders

Long Non-coding RNAs and Circular RNAs: Insights Into Microglia and Astrocyte Mediated Neurological Diseases

Phillyrin Prevents Neuroinflammation-Induced Blood–Brain Barrier Damage Following Traumatic Brain Injury via Altering Microglial Polarization

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