Intranasal Delivery of lincRNA-Cox2 siRNA Loaded Extracellular Vesicles Decreases Lipopolysaccharide-Induced Microglial Proliferation in Mice

Liao, Ke; Niu, Fang; Dagur, Raghubendra Singh; He, Mengfan; Tian, Changhai; Hu, Guoku

doi:10.1007/s11481-019-09864-z

Cited by 39 publications

(38 citation statements)

References 32 publications

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“…Our group has also developed EV-loaded RNA drug target(s) as therapeutics. For example, our in vivo study, for the first time, demonstrated that intranasal delivery of lincRNA-Cox2 siRNA restored microglial phagocytic activity of morphine-administered mice [ 201 ] as well as LPS-induced microglial proliferation in mice [ 202 ]. These findings could have ramifications for the development of intranasal delivery of EV-loaded small RNA that could serve as therapeutics for a multitude of neurodegenerative disorders, including those associated with neuroinflammation.…”

Section: Evs As Biomarkers and Therapeutic Vehicles For Viral Infementioning

confidence: 99%

Extracellular Vesicles in Viral Infections of the Nervous System

Kutchy

Peeples

Sil

et al. 2020

Viruses

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Almost all types of cells release extracellular vesicles (EVs) into the extracellular space. EVs such as exosomes and microvesicles are membrane-bound vesicles ranging in size from 30 to 1000 nm in diameter. Under normal conditions, EVs mediate cell to cell as well as inter-organ communication via the shuttling of their cargoes which include RNA, DNA and proteins. Under pathological conditions, however, the number, size and content of EVs are found to be altered and have been shown to play crucial roles in disease progression. Emerging studies have demonstrated that EVs are involved in many aspects of viral infection-mediated neurodegenerative diseases. In the current review, we will describe the interactions between EV biogenesis and the release of virus particles while also reviewing the role of EVs in various viral infections, such as HIV-1, HTLV, Zika, CMV, EBV, Hepatitis B and C, JCV, and HSV-1. We will also discuss the potential uses of EVs and their cargoes as biomarkers and therapeutic vehicles for viral infections.

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Section: Evs As Biomarkers and Therapeutic Vehicles For Viral Infementioning

confidence: 99%

Extracellular Vesicles in Viral Infections of the Nervous System

Kutchy

Peeples

Sil

et al. 2020

Viruses

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“…Many studies have suggested a bidirectional transport of EVs from the brain to the systemic circulation via the BBB [19][20][21]. For example, systemic delivery of EVs from dendritic cells (DCs) loaded with the small interfering RNA (siRNA) were used as therapeutic vehicles to treat a mouse model of Alzheimer'sdisease [21], suggesting thereby the ability of these vehicles to cross the BBB and deliver the siRNA cargo into target cells for specific gene knockdown [22]. In another study EVs derived from a mouse lymphoma cell line were demonstrated to deliver curcumin across the BBB into microglial cells via the intranasal administration route to attenuate neuroinflammation and autoimmune responses in an experimental autoimmune encephalomyelitis (EAE) model [23].…”

Section: Introductionmentioning

confidence: 99%

Neuronal‐derived extracellular vesicles are enriched in the brain and serum of HIV‐1 transgenic rats

Dagur

Liao

Sil

et al. 2019

J of Extracellular Vesicle

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Despite the efficacy of combination antiretroviral therapy (ART) in controlling human immunodeficiency virus (HIV-1) replication, cytotoxic viral proteins such as HIV-1 transactivator of transcription (Tat) persist in tissues such as the brain. Although HIV-1 does not infect neuronal cells, it is susceptible to viral Tat protein-mediated toxicity, leading to neuroinflammation that underlies HIV-associated neurocognitive disorders (HAND). Given the role of extracellular vesicles (EVs) in both cellular homoeostasis and under pathological conditions, we sought to investigate the alterations in the quantity of neuronal-derived EVs in the brainas defined by the presence of cell adhesion molecule L1 (L1CAM) and to evaluate the presence of L1CAM + EVs in the peripheral circulation of HIV-1 transgenic (HIV-1 Tg) rats. The primary goal of this study was to investigate the effect of long-term exposure of HIV-1 viral proteins on the release of neuronal EVs in the brain and their transfer in the systemic compartment. Brain and serum EVs were isolated from both wild type and HIV-1 Tg rats using differential ultracentrifugation with further purification using the Optiprep gradient method. The subpopulation of neuronal EVs was further enriched using immunoprecipitation. The current findings demonstrated increased presence of L1CAM + neuronal-derived EVs both in the brain and serum of HIV-1 Tg rats.

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“…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). Recently, lincRNA-Cox2 has been shown to control cell cycle gene expression and that silencing of lincRNA-Cox2 reduces LPS-induced microglial proliferation (64).…”

Section: Discussionmentioning

confidence: 99%

“…Targeted inhibition of proin ammatory pathways in microglia may reduce neurotoxicity and help mitigate or treat such neuroin ammatory disorders (6). A few studies have shown that siRNA delivery to the CNS can exacerbate or reduce aspects of lincRNA-regulated microglial proin ammatory responses in vivo (35,64,73,74) indicating their utility when the lincRNA function is fully understood. Our proof-of-concept, in vitro, co-culture experiments showed that silencing of Nostrill in microglia inhibits LPS-stimulated neurotoxicity while overexpression of Nostrill leads to neurotoxicity (Fig.…”

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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Intranasal Delivery of lincRNA-Cox2 siRNA Loaded Extracellular Vesicles Decreases Lipopolysaccharide-Induced Microglial Proliferation in Mice

Cited by 39 publications

References 32 publications

Extracellular Vesicles in Viral Infections of the Nervous System

Extracellular Vesicles in Viral Infections of the Nervous System

Neuronal‐derived extracellular vesicles are enriched in the brain and serum of HIV‐1 transgenic rats

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

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