LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

Wan, Pin; Su, Wenru; Zhang, Yingying; Liu, Zhidong; Deng, Caibin; Li, Jinmiao; Jiang, Nan; Huang, Siyu; Long, Erping; Zhuo, Yehong

doi:10.1038/s41418-019-0351-4

Cited by 201 publications

(175 citation statements)

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“…The lncRNAs frequently form competing endogenous RNA (ceRNA) regulatory networks wherein they modulate the expression of downstream genes by competitively binding to microRNAs (miRNAs) 23 , 24 . CeRNA networks regulating pryoptosis have been reported in different cells types 25 , 26 , including neurons 27 . In this study, we screened differentially expressed lncRNAs and mRNAs between SCI group and sham-operated group, WT group and TLR4 −/− group using RNA sequencing.…”

Section: Introductionmentioning

confidence: 99%

TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

et al. 2020

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Neuroinflammation plays a crucial role in the secondary phase of spinal cord injury (SCI), and is initiated following the activation of toll-like receptor 4 (TLR4). However, the downstream mechanism remains unknown. Pyroptosis is a form of inflammatory programmed cell death, which is closely involved in neuroinflammation, and it can be regulated by TLR4 according to a recent research. In addition, several studies have shown that long non-coding RNAs (lncRNAs) based mechanisms were related to signal transduction downstream of TLR4 in the regulation of inflammation. Thus, in this study, we want to determine whether TLR4 can regulate pyroptosis after SCI via lncRNAs. Our results showed that TLR4 was activated following SCI and promoted the expression of lncRNA-F630028O10Rik. This lncRNA functioned as a ceRNA for miR-1231-5p/Col1a1 axis and enhanced microglial pyroptosis after SCI by activating the PI3K/AKT pathway. Furthermore, we determined STAT1 was the upstream transcriptional factor of IncRNA-F630028O10Rik and was induced by the damage-responsive TLR4/MyD88 signal. Our findings provide new insights and a novel therapeutic strategy for treating SCI.

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Section: Introductionmentioning

confidence: 99%

TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

et al. 2020

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“… 17 A recent report revealed that H19 regulated inflammation and nerve injury via directly sponging miR-21 to promote the expression of PDCA4 in retinal ischemia/reperfusion injury. 18 However, whether miR-21 could be regulated by H19 in children with asthma remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

LncRNA H19 Inhibits Proliferation and Migration of Airway Smooth Muscle Cells Induced by PDGF-BB Through miR-21/PTEN/Akt Axis

Yu¹,

Qi²,

Zhou³

2021

JAA

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Background LncRNA H19 expression is down-regulated in patients with asthma. The hyperplasia of airway smooth muscle cells (ASMCs) promotes the development of airway remodeling in asthma. Therefore, we attempted to evaluate the regulatory function of H19 in the proliferation and migration of ASMCs. Methods The expressions of H19 and miR-21 were detected using qRT-PCR. PDGF-BB-induced abnormal proliferation and migration of ASMCs was used as the airway remodeling model in vitro. The expressions of H19 and miR-21 were modified by transfection with pcDNA3.1-H19 and miR-21 mimic, respectively. CCK-8 assay, flow cytometry-based cell cycle analysis was conducted to examine the proliferation ability of ASMCs. The migration ability was measured by transwell assay. Dual-luciferase reporter system was carried out to find the potential relationship between miR-21 and H19 or PTEN. Western blot was conducted to detect the expressions of PCNA, MMP-9, α-SMA, PTEN, and the phosphorylation level of Akt. Results LncRNA-H19 expression was decreased and microRNA-21 expression was increased in serum samples of children with asthma and PDGF-BB-stimulated ASMCs. Overexpression of H19 reduced the proliferation and migration ability of ASMCs with PDGF-BB treatment and these changes were reversed by miR-21 mimic. H19 promoted the protein level of PTEN via sponging miR-21. Overexpression of H19 suppressed miR-21-induced phosphorylation of Akt, and the suppression effect of H19 on phosphorylation of Akt was significantly reduced after transfecting shPTEN in ASMCs. Conclusion In this study, overexpression of H19 suppressed the proliferation and migration of ASMCs induced by PDGF-BB via miR-21/PTEN/Akt axis, which could be a potential biomarker and target for treating hyperplasia of airway smooth muscle cells.

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“…The biological importance of exosomes and exosomal-miRNA (exoMiR) is reflected by their association with a range of inflammatory ( Van Hezel et al, 2017 ; Cypryk et al, 2018 ), autoimmune ( Long et al, 2018 ; Anel et al, 2019 ) and neurodegenerative diseases ( Jan et al, 2017 ; Soria et al, 2017 ; Jain et al, 2019 ). These include diabetes ( Saeedi et al, 2018 ), rheumatoid arthritis ( Skriner et al, 2006 ; Zhang et al, 2006 ; Wan et al, 2019 ), and Alzheimer’s and Parkinson’s disease ( Gupta and Pulliam, 2014 ; Li et al, 2018 ; Jain et al, 2019 ; Sackmann et al, 2019 ). exoMiR have been reported to play pathogenic roles in these diseases by promoting angiogenesis ( Kosaka et al, 2013 ; Atienzar−Aroca et al, 2016 ), and modulating immune responses, including in the recruitment of immune cells ( Théry et al, 2002 ; Abusamra et al, 2005 ; Robbins and Morelli, 2014 ; Ye et al, 2014 ; Wong et al, 2016 ; Van Hezel et al, 2017 ); features that contribute to cell death.…”

Section: Introductionmentioning

confidence: 99%

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

Wooff

Cioanca

Chu-Tan

et al. 2020

Front. Cell. Neurosci.

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Photoreceptor cell death and inflammation are known to occur progressively in retinal degenerative diseases such as age-related macular degeneration (AMD). However, the molecular mechanisms underlying these biological processes are largely unknown. Extracellular vesicles (EV) are essential mediators of cell-to-cell communication with emerging roles in the modulation of immune responses. EVs, including exosomes, encapsulate and transfer microRNA (miRNA) to recipient cells and in this way can modulate the environment of recipient cells. Dysregulation of EVs however is correlated to a loss of cellular homeostasis and increased inflammation. In this work we investigated the role of isolated retinal small-medium sized EV (s-mEV) which includes exosomes in both the healthy and degenerating retina. Isolated s-mEV from normal retinas were characterized using dynamic light scattering, transmission electron microscopy and western blotting, and quantified across 5 days of photo-oxidative damage-induced degeneration using nanotracking analysis. Small RNAseq was used to characterize the miRNA cargo of retinal s-mEV isolated from healthy and damaged retinas. Finally, the effect of exosome inhibition on cell-to-cell miRNA transfer and immune modulation was conducted using systemic daily administration of exosome inhibitor GW4869 and in situ hybridization of s-mEV-abundant miRNA, miR-124-3p. Electroretinography and immunohistochemistry was performed to assess functional and morphological changes to the retina as a result of GW4869-induced exosome depletion. Results demonstrated an inverse correlation between s-mEV concentration and photoreceptor survivability, with a decrease in s-mEV numbers following degeneration. Small RNAseq revealed that s-mEVs contained uniquely enriched miRNAs in comparison to in whole retinal tissue, however, there was no differential change in the s-mEV miRNAnome following photo-oxidative damage. Exosome inhibition via the use of GW4869 was also found to exacerbate retinal degeneration, with reduced retinal function and increased levels of inflammation and cell death demonstrated following photo-oxidative damage in exosome-inhibited mice. Further, GW4869-treated mice displayed impaired translocation of photoreceptor-derived miR-124-3p to the inner retina during damage. Taken together, we propose that retinal s-mEV and their miRNA cargo play an essential role in maintaining retinal homeostasis through immune-modulation, and have the potential to be used in targeted gene therapy for retinal degenerative diseases.

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LncRNA H19 initiates microglial pyroptosis and neuronal death in retinal ischemia/reperfusion injury

Cited by 201 publications

References 53 publications

TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

TLR4 promotes microglial pyroptosis via lncRNA-F630028O10Rik by activating PI3K/AKT pathway after spinal cord injury

LncRNA H19 Inhibits Proliferation and Migration of Airway Smooth Muscle Cells Induced by PDGF-BB Through miR-21/PTEN/Akt Axis

Small-Medium Extracellular Vesicles and Their miRNA Cargo in Retinal Health and Degeneration: Mediators of Homeostasis, and Vehicles for Targeted Gene Therapy

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