Downregulation of LncRNA<i>TUG1</i>Inhibited TLR4 Signaling Pathway-Mediated Inflammatory Damage After Spinal Cord Ischemia Reperfusion in Rats via Suppressing TRIL Expression

Jia, Hui; Ma, Hong; Li, Zhe; Chen, Fengshou; Fang, Bo; Cao, Xun; Chang, Yi Wen; Qiang, Ziyun

doi:10.1093/jnen/nly126

Cited by 50 publications

(27 citation statements)

References 39 publications

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“…We confirmed that Tril is mostly expressed in POMC neurons (8). In addition, as it could be expected for a TLR4-associated protein, Tril was detected in microglia (32). Using two distinct mouse strains, we showed that hypothalamic Tril is regulated by the consumption of a HFD, as other inflammatory proteins involved in the development of hypothalamic abnormalities in DIO (2,3,5,33,34).…”

Section: Discussionsupporting

confidence: 81%

POMC-specific knockdown of Tril reduces body adiposity and increases hypothalamic leptin responsiveness

Moura‐Assis

Nogueira

de-Lima-Júnior

et al. 2020

Preprint

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In a public dataset of transcripts differentially expressed in selected neuronal subpopulations of the arcuate nucleus, we identified TLR4-interactor with leucine-rich repeats (Tril) as a potential candidate for mediating the harmful effects of a high-fat diet in proopiomelanocortin (POMC) neurons. The non-cell-specific inhibition of Tril in the arcuate nucleus resulted in reduced hypothalamic inflammation, protection against diet-induced obesity associated with increased whole-body energy expenditure and increased systemic glucose tolerance. The inhibition of Tril, specifically in POMC neurons, resulted in a trend for protection against diet-induced obesity, increased energy expenditure and increased hypothalamic sensitivity to leptin. Thus, Tril emerges as a new component of the complex mechanisms that promote hypothalamic dysfunction in experimental diet-induced obesity.

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Section: Discussionsupporting

confidence: 81%

POMC-specific knockdown of Tril reduces body adiposity and increases hypothalamic leptin responsiveness

Moura‐Assis

Nogueira

de-Lima-Júnior

et al. 2020

Preprint

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“…Four independent experiments were repeated, with three replicates each time, *p < 0.05, **p < 0.01, ***p < 0.001. in the pathogenesis in ischemic stroke. Abundant studies pointed out that lncRNA TUG1 was actively involved in I/R-related inflammatory response (Chen et al, 2017;Jia et al, 2019;Su et al, 2019;Yang et al, 2019;Liang et al, 2020;Xu et al, 2020). For example, OGD/R injury could upregulate the expression of TUG1 in cultured MA-C cells and subsequently contributed to neuronal death by sponging miR-145 and directly inhibiting the expression of AQP4 (encoding aquaporin 4) (Shan et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

LncRNA TUG1 Demethylated by TET2 Promotes NLRP3 Expression, Contributes to Cerebral Ischemia/Reperfusion Inflammatory Injury

et al. 2021

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LncRNA TUG1 has not yet been reported in cerebral ischemia/reperfusion (I/R) injury. Methylcytosine dioxygenase TET2 is involved in ischemic damage. This study aimed to investigate the effects of TUG1 demethylated by TET2 on I/R-induced inflammatory response and identified its possible mechanisms.We found that TUG1 expression was significantly upregulated in oxygen-glucose deprivation and reoxygenation (OGD/R)-induced SH-SY5Y and SK-N-SH cells. Using the middle cerebral artery occlusion (MCAO) mice, we observed a similar effect. We also found that I/R injury could downregulate miR-200a-3p and upregulate NLRP3 and TET2. The knockdown of TUG1 could alleviate OGD/R-induced inflammatory response through upregulating miR-200a-3p and downregulating NLRP3 and other pro-inflammatory molecules. miR-200a-3p inhibition can partially reverse the effects of TUG1 silencing. Further experiments confirmed that TUG1 sponged miR-200a-3p to diminish miR-200a-3p and promote NLRP3 dependent inflammatory responses. Mechanically, knockdown of TET2 induced low levels of TUG1 and high levels of miR-200a-3p in both SK-N-SH and SH-SY5Y cells. IL-18, IL-1β, NLRP3, Caspase-1, and GSDMD-N were highly downregulated in OGD/R-induced SK-N-SH and SH-SY5Y cells after TET2 knockdown. TUG1 overexpression could reverse this effect. All the data indicated that TET2 could demethylate TUG1 and contribute to the inflammatory response. In additional experiments using the MCAO mice model, we confirmed knockdown of TET2 attenuated I/R-induced inflammatory response and brain injuries via decreasing TUG1 and increasing miR-200a-3p to inhibit NLRP3 expression. The demethylation of TUG1 by TET2 might aggravate I/R-induced inflammatory injury via modulating NLRP3 by miR-200a-3p. Our data confirmed that TET2 contributed to I/R-induced inflammatory response via the demethylation of TUG1 and regulated TUG1/miR-200a-3p/NLRP3 pathway.

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“…These data suggest that Nostrill is important during the beginning stages of microglial activation to a pro-in ammatory state and not an anti-in ammatory state. A handful of lncRNAs such as lincRNA-Cox2 (31,37), lincRNA p21 (36) lncRNA H19 (55), lncRNA HOTAIR (56,57), lncRNA MALAT1 (58,59) and lncRNA TUG1 (60,61) have also been shown to participate in driving pro-in ammatory polarization of microglia. LincRNA-Cox2 regulates several immune responsive genes in both in vitro and in vivo systems including lincRNA-Cox2-de cient mice (31,37,62,63).…”

Section: Discussionmentioning

confidence: 99%

A novel long non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia.

Mathy

Burleigh

Kochvar

et al. 2020

Preprint

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Background Microglia are resident immunocompetent and phagocytic cells in the CNS. Pro-inflammatory microglia, stimulated by environmental microbial signals such as bacterial lipopolysaccharide (LPS), viral RNAs, or inflammatory cytokines, are neurotoxic and associated with pathogenesis of several neurodegenerative diseases. Long non-coding RNA (lncRNA) are emerging as important tissue-specific regulators directing cell differentiation and functional states and may help direct proinflammatory responses of microglia. Methods Microglial gene expression array analyses and qRT-PCR was used to identify a novel intergenic long-noncoding RNA that was upregulated in LPS-stimulated microglial cell lines, LPS-stimulated primary microglia, and LPS-injected mouse cortical tissue. Silencing and overexpression studies, RNA immunoprecipitation, chromatin immunoprecipitation, chromatin RNA immunoprecipitation assays, and qRT-PCR were used to study the function of this long-noncoding RNA in microglia. In vitro cytotoxicity assays were used to examine the effects of silencing the novel long-noncoding RNA in LPS-stimulated microglia on neurotoxicity. Results We report here that the previously uncharacterized intergenic lncRNA we termed Nostrill is induced by LPS stimulation in both BV2 cells and primary murine microglia, as well as in cortical tissue of LPS-injected mice. Induction of Nostrill is NF-κB dependent and silencing of Nostrill decreased inducible nitric oxide synthase (iNOS) expression and nitric oxide production in BV2 and primary microglial cells. Overexpression of Nostrill increased iNOS expression and nitric oxide production. RNA immunoprecipitation assays demonstrated that Nostrill is physically associated with NF-κB subunit p65 following LPS stimulation. Silencing of Nostrill significantly reduced NF-κB p65 and RNA polymerase II recruitment to the iNOS promoter and decreased H3K4me3 activating histone modifications at iNOS gene loci. In vitro studies demonstrate that silencing of Nostrill in microglia reduced LPS-stimulated microglia neurotoxicity. Conclusions Our data indicate a new regulatory role of NF-κB-induced Nostrill and suggest that Nostrill acts as a co-activator of transcription of iNOS resulting in the production of nitric oxide in microglia through modulation of epigenetic chromatin remodeling. Nostrill may be a target for reducing the neurotoxicity associated with iNOS-mediated inflammatory processes in microglia during neurodegeneration.

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Downregulation of LncRNATUG1Inhibited TLR4 Signaling Pathway-Mediated Inflammatory Damage After Spinal Cord Ischemia Reperfusion in Rats via Suppressing TRIL Expression

Cited by 50 publications

References 39 publications

POMC-specific knockdown of Tril reduces body adiposity and increases hypothalamic leptin responsiveness

POMC-specific knockdown of Tril reduces body adiposity and increases hypothalamic leptin responsiveness

LncRNA TUG1 Demethylated by TET2 Promotes NLRP3 Expression, Contributes to Cerebral Ischemia/Reperfusion Inflammatory Injury

A novel long non-coding RNA, Nostrill, regulates iNOS gene transcription and neurotoxicity in microglia.

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