scholarly journals Small Extracellular Vesicle Enrichment of a Retrotransposon-Derived Double-Stranded RNA: A Means to Avoid Autoinflammation?

Biomedicines ◽  
2021 ◽  
Vol 9 (9) ◽  
pp. 1136
Author(s):  
Marilou H. Barrios ◽  
Alexandra L. Garnham ◽  
Andrew D. Foers ◽  
Lesley Cheng-Sim ◽  
Seth L. Masters ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Cell Types ◽  
Bioinformatic Analysis ◽  
Extracellular Vesicle ◽  
Interferon Response ◽  
Type I ◽  
Double Stranded Rna ◽  
Multiple Cell ◽  
Toxic Rna ◽  
Cellular Components

Small extracellular vesicles (SEVs) such as exosomes are released by multiple cell types. Originally believed to be a mechanism for selectively removing unwanted cellular components, SEVs have received increased attention in recent years for their ability to mediate intercellular communication. Apart from proteins and lipids, SEVs contain RNAs, but how RNAs are selectively loaded into SEVs remains poorly understood. To address this question, we profiled SEV RNAs from mouse dendritic cells using RNA-Seq and identified a long noncoding RNA of retroviral origin, VL30, which is highly enriched (>200-fold) in SEVs compared to parental cells. Bioinformatic analysis revealed that exosome-enriched isoforms of VL30 RNA contain a repetitive 26-nucleotide motif. This repeated motif is itself efficiently incorporated into SEVs, suggesting the likelihood that it directly promotes SEV loading. RNA folding analyses indicate that the motif is likely to form a long double-stranded RNA hairpin and, consistent with this, its overexpression was associated with induction of a potent type I interferon response. Taken together, we propose that preferential loading into SEVs of the VL30 RNA containing this immunostimulatory motif enables cells to remove a potentially toxic RNA and avoid autoinflammation. In this way, the original notion of SEVs as a cellular garbage bin should not be entirely discounted.

scholarly journals Nc886, a Novel Suppressor of the Type I Interferon Response Upon Pathogen Intrusion

2021 ◽  
Vol 22 (4) ◽  
pp. 2003
Author(s):  
Yeon-Su Lee ◽  
Xiaoyong Bao ◽  
Hwi-Ho Lee ◽  
Jiyoung Joan Jang ◽  
Enkhjin Saruuldalai ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Cell Types ◽  
Innate Immune ◽  
Interferon Response ◽  
Type I ◽  
Activator Protein 1 ◽  
Innate Immune Responses ◽  
Protein Kinase R ◽  
Crucial Component ◽  
Molecular Patterns

Interferons (IFNs) are a crucial component in the innate immune response. Especially the IFN-β signaling operates in most cell types and plays a key role in the first line of defense upon pathogen intrusion. The induction of IFN-β should be tightly controlled, because its hyperactivation can lead to tissue damage or autoimmune diseases. Activation of the IFN-β promoter needs Interferon Regulatory Factor 3 (IRF3), together with Nuclear Factor kappa-light-chain-enhancer of activated B cells (NF-κB) and Activator Protein 1 (AP-1). Here we report that a human noncoding RNA, nc886, is a novel suppressor for the IFN-β signaling and inflammation. Upon treatment with several pathogen-associated molecular patterns and viruses, nc886 suppresses the activation of IRF3 and also inhibits NF-κB and AP-1 via inhibiting Protein Kinase R (PKR). These events lead to decreased expression of IFN-β and resultantly IFN-stimulated genes. nc886′s role might be to restrict the IFN-β signaling from hyperactivation. Since nc886 expression is regulated by epigenetic and environmental factors, nc886 might explain why innate immune responses to pathogens are variable depending on biological settings.

scholarly journals Spatial deconvolution of HER2-positive breast cancer delineates tumor-associated cell type interactions

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alma Andersson ◽  
Ludvig Larsson ◽  
Linnea Stenbeck ◽  
Fredrik Salmén ◽  
Anna Ehinger ◽  
...  
Keyword(s):  
Spatial Information ◽  
Cell Types ◽  
Interferon Response ◽  
Type I ◽  
Cellular Interactions ◽  
Her2 Positive ◽  
High Resolution Map ◽  
Functional Relevance ◽  
Macrophage Subset ◽  
Treatment And Diagnosis

AbstractIn the past decades, transcriptomic studies have revolutionized cancer treatment and diagnosis. However, tumor sequencing strategies typically result in loss of spatial information, critical to understand cell interactions and their functional relevance. To address this, we investigate spatial gene expression in HER2-positive breast tumors using Spatial Transcriptomics technology. We show that expression-based clustering enables data-driven tumor annotation and assessment of intra- and interpatient heterogeneity; from which we discover shared gene signatures for immune and tumor processes. By integration with single cell data, we spatially map tumor-associated cell types to find tertiary lymphoid-like structures, and a type I interferon response overlapping with regions of T-cell and macrophage subset colocalization. We construct a predictive model to infer presence of tertiary lymphoid-like structures, applicable across tissue types and technical platforms. Taken together, we combine different data modalities to define a high resolution map of cellular interactions in tumors and provide tools generalizing across tissues and diseases.

scholarly journals Location Matters: Navigating Regional Heterogeneity of the Neurovascular Unit

2021 ◽  
Vol 15 ◽  
Author(s):  
Louis-Philippe Bernier ◽  
Clément Brunner ◽  
Azzurra Cottarelli ◽  
Matilde Balbi
Keyword(s):  
Brain Function ◽  
Energy Demand ◽  
Neurovascular Unit ◽  
Cell Types ◽  
Brain Regions ◽  
Regional Heterogeneity ◽  
Regional Specialization ◽  
Multiple Cell ◽  
Cellular Components ◽  
The Brain

The neurovascular unit (NVU) of the brain is composed of multiple cell types that act synergistically to modify blood flow to locally match the energy demand of neural activity, as well as to maintain the integrity of the blood-brain barrier (BBB). It is becoming increasingly recognized that the functional specialization, as well as the cellular composition of the NVU varies spatially. This heterogeneity is encountered as variations in vascular and perivascular cells along the arteriole-capillary-venule axis, as well as through differences in NVU composition throughout anatomical regions of the brain. Given the wide variations in metabolic demands between brain regions, especially those of gray vs. white matter, the spatial heterogeneity of the NVU is critical to brain function. Here we review recent evidence demonstrating regional specialization of the NVU between brain regions, by focusing on the heterogeneity of its individual cellular components and briefly discussing novel approaches to investigate NVU diversity.

scholarly journals Selective extracellular vesicle-mediated export of an overlapping set of microRNAs from multiple cell types

BMC Genomics ◽  
2012 ◽  
Vol 13 (1) ◽  
pp. 357 ◽  
Author(s):  
Jasenka Guduric-Fuchs ◽  
Anna O’Connor ◽  
Bailey Camp ◽  
Christina L O'Neill ◽  
Reinhold J Medina ◽  
...  
Keyword(s):  
Cell Types ◽  
Extracellular Vesicle ◽  
Multiple Cell

scholarly journals Endogenous mitochondrial double‐stranded RNA is not an activator of the type I interferon response in human pancreatic beta cells

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra Coomans de Brachène ◽  
Angela Castela ◽  
Anyïshai E. Musuaya ◽  
Lorella Marselli ◽  
Piero Marchetti ◽  
...  
Keyword(s):  
Beta Cells ◽  
Pancreatic Beta Cells ◽  
Viral Infections ◽  
Human Islets ◽  
Interferon Response ◽  
Interferon Α ◽  
Type I ◽  
Type I Ifn ◽  
Danger Signal ◽  
Double Stranded Rna

Abstract Background Type 1 diabetes (T1D) is an autoimmune disease characterized by the progressive destruction of pancreatic beta cells. Interferon-α (IFNα), an antiviral cytokine, is expressed in the pancreatic islets in early T1D, which may be secondary to viral infections. However, not all patients harboring a type I IFN signature present signals of viral infection, suggesting that this response might be initiated by other “danger signals”. Accumulation of mitochondrial double-stranded RNA (mtdsRNA; a danger signal), secondary to silencing of members of the mitochondrial degradosome, PNPT1 and SUV3, has been described to activate the innate immune response. Methods To evaluate whether mtdsRNA represents a “danger signal” for pancreatic beta cells in the context of T1D, we silenced PNPT1 and/or SUV3 in slowly proliferating human insulin-secreting EndoC-βH1 cells and in non-proliferating primary human beta cells and evaluated dsRNA accumulation by immunofluorescence and the type I IFN response by western blotting and RT-qPCR. Results Only the simultaneous silencing of PNPT1/SUV3 induced dsRNA accumulation in EndoC-βH1 cells but not in dispersed human islets, and there was no induction of a type I IFN response. By contrast, silencing of these two genes individually was enough to induce dsRNA accumulation in fibroblasts present in the human islet preparations. Conclusions These data suggest that accumulation of endogenous mtdsRNA following degradosome knockdown depends on the proliferative capacity of the cells and is not a mediator of the type I IFN response in human pancreatic beta cells.

scholarly journals Mechanisms of Action of MiRNAs and LncRNAs in Extracellular Vesicle in Atherosclerosis

2021 ◽  
Vol 8 ◽  
Author(s):  
Hui Xu ◽  
Yu-Qing Ni ◽  
You-Shuo Liu
Keyword(s):  
Cell Communication ◽  
Cell Types ◽  
Extracellular Vesicle ◽  
Chronic Inflammatory Disease ◽  
Myocardial Infarctions ◽  
Diagnostic Biomarkers ◽  
Multiple Cell ◽  
Artery Disease ◽  
Intercellular Communications ◽  
Progression Of Atherosclerosis

Atherosclerosis, a complex chronic inflammatory disease, involves multiple alterations of diverse cells, including endothelial cells (ECs), vascular smooth muscle cells (VSMCs), monocytes, macrophages, dendritic cells (DCs), platelets, and even mesenchymal stem cells (MSCs). Globally, it is a common cause of morbidity as well as mortality. It leads to myocardial infarctions, stroke and disabling peripheral artery disease. Extracellular vesicles (EVs) are a heterogeneous group of cell-derived membranous structures that secreted by multiple cell types and play a central role in cell-to-cell communication by delivering various bioactive cargos, especially microRNAs (miRNAs) and long non-coding RNAs (lncRNAs). Emerging evidence demonstrated that miRNAs and lncRNAs in EVs are tightly associated with the initiation and development of atherosclerosis. In this review, we will outline and compile the cumulative roles of miRNAs and lncRNAs encapsulated in EVs derived from diverse cells in the progression of atherosclerosis. We also discuss intercellular communications via EVs. In addition, we focused on clinical applications and evaluation of miRNAs and lncRNAs in EVs as potential diagnostic biomarkers and therapeutic targets for atherosclerosis.

scholarly journals MicroRNA-deficient mouse embryonic stem cells acquire a functional interferon response

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Jeroen Witteveldt ◽  
Lisanne I Knol ◽  
Sara Macias
Keyword(s):  
Stem Cells ◽  
Embryonic Stem Cells ◽  
Mammalian Cells ◽  
Viral Infections ◽  
Embryonic Stem ◽  
Cell Types ◽  
Interferon Response ◽  
Central Component ◽  
Type I ◽  
Antiviral Mechanism

When mammalian cells detect a viral infection, they initiate a type I interferon (IFNs) response as part of their innate immune system. This antiviral mechanism is conserved in virtually all cell types, except for embryonic stem cells (ESCs) and oocytes which are intrinsically incapable of producing IFNs. Despite the importance of the IFN response to fight viral infections, the mechanisms regulating this pathway during pluripotency are still unknown. Here we show that, in the absence of miRNAs, ESCs acquire an active IFN response. Proteomic analysis identified MAVS, a central component of the IFN pathway, to be actively silenced by miRNAs and responsible for suppressing IFN expression in ESCs. Furthermore, we show that knocking out a single miRNA, miR-673, restores the antiviral response in ESCs through MAVS regulation. Our findings suggest that the interaction between miR-673 and MAVS acts as a switch to suppress the antiviral IFN during pluripotency and present genetic approaches to enhance their antiviral immunity.

scholarly journals Nicastrin haploinsufficiency alters expression of type-I interferon-stimulated genes in two immortalized human cell lines

2018 ◽  
Author(s):  
Li Cao ◽  
David J. Morales-Heil ◽  
Elisha D. O. Roberson
Keyword(s):  
Cell Line ◽  
Cell Lines ◽  
Rare Variants ◽  
Type I Interferon ◽  
Human Keratinocytes ◽  
Cell Types ◽  
Interferon Response ◽  
Luciferase Reporter ◽  
Type I ◽  
Loss Of Function

A.AbstractBackgroundHidradenitis suppurativa (HS) is a chronic skin disease. The symptoms can be severe, and include intensely painful nodules and abscesses in apocrine-gland rich inverse skin, such as the buttocks, under the arms, and the groin. Autosomal dominant forms of HS exist, but are rare. Some of these kindred have heterozygous loss-of-function rare variants in the γ-secretase complex component nicastrin (NCSTN).ObjectivesWe wanted to know what effect NCSTN haploinsufficiency has on human keratinocytes to assess potential mechanisms for lesion development.MethodsWe knocked down nicastrin using an shRNA construct in both a keratinocyte cell line (HEK001) and an embryonic kidney cell line (HEK293). We assessed differential gene expression using RNA microarray. We also generated a NCSTN heterozygous deletion in the HEK293 line using CRISPR/Cas9 genome-editing and assessed NFKB activity in this line using a luciferase reporter.ResultsThe keratinocyte NCSTN knockdown cell line demonstrated significantly increased expression of genes related to the type-I interferon response pathway when compared to controls. Both HEK001 and HEK293 knockdowns demonstrated evidence for altered growth. We observed a small, but significant increase in NFKB signaling in response to TNF treatment a HEK293 line genome-edited for reduced NCSTN.ConclusionsOur data suggest a role for increased keratinocyte inflammatory responsiveness in familial HS. Confirming this phenotype, and characterizing additional effects in different cell types, will require study beyond cell lines in primary cells and tissues.

scholarly journals Ancient exapted transposable elements promote nuclear enrichment of human long noncoding RNAs

2017 ◽  
Author(s):  
Joana Carlevaro-Fita ◽  
Taisia Polidori ◽  
Monalisa Das ◽  
Carmen Navarro ◽  
Tatjana I. Zoller ◽  
...  
Keyword(s):  
Transposable Elements ◽  
Long Noncoding Rna ◽  
Noncoding Rna ◽  
Cell Types ◽  
Subcellular Localisation ◽  
Evolutionary Selection ◽  
Dependent Relationship ◽  
Evolutionarily Conserved ◽  
Show Evidence ◽  
Multiple Cell

AbstractThe sequence domains underlying long noncoding RNA (lncRNA) activities, including their characteristic nuclear enrichment, remain largely unknown. It has been proposed that these domains can originate from neofunctionalised fragments of transposable elements (TEs), otherwise known as RIDLs (Repeat Insertion Domains of Long Noncoding RNA), although just a handful have been identified. It is challenging to distinguish functional RIDL instances against a numerous genomic background of neutrally-evolving TEs. We here show evidence that a subset of TE types experience evolutionary selection in the context of lncRNA exons. Together these comprise an enrichment group of 5374 TE fragments in 3566 loci. Their host lncRNAs tend to be functionally validated and associated with disease. This RIDL group was used to explore the relationship between TEs and lncRNA subcellular localisation. Using global localisation data from ten human cell lines, we uncover a dose-dependent relationship between nuclear/cytoplasmic distribution, and evolutionarily-conserved L2b, MIRb and MIRc elements. This is observed in multiple cell types, and is unaffected by confounders of transcript length or expression. Experimental validation with engineered transgenes shows that these TEs drive nuclear enrichment in a natural sequence context. Together these data reveal a role for TEs in regulating the subcellular localisation of lncRNAs.

scholarly journals Characterization and comparative analysis of transcriptional profiles of porcine colostrum and mature milk at different parities

2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Brittney N. Keel ◽  
Amanda K. Lindholm-Perry ◽  
William T. Oliver ◽  
James E. Wells ◽  
Shuna A. Jones ◽  
...  
Keyword(s):  
Mammary Epithelial Cells ◽  
Milk Proteins ◽  
Cell Types ◽  
Mammary Epithelial ◽  
Mature Milk ◽  
Milk Samples ◽  
Whole Milk ◽  
Main Effect ◽  
Multiple Cell ◽  
Cellular Components

Abstract Background Porcine milk is a complex fluid, containing a myriad of immunological, biochemical, and cellular components, made to satisfy the nutritional requirements of the neonate. Whole milk contains many different cell types, including mammary epithelial cells, neutrophils, macrophages, and lymphocytes, as well nanoparticles, such as milk exosomes. To-date, only a limited number of livestock transcriptomic studies have reported sequencing of milk. Moreover, those studies focused only on sequencing somatic cells as a proxy for the mammary gland with the goal of investigating differences in the lactation process. Recent studies have indicated that RNA originating from multiple cell types present in milk can withstand harsh environments, such as the digestive system, and transmit regulatory molecules from maternal to neonate. Transcriptomic profiling of porcine whole milk, which is reflective of the combined cell populations, could help elucidate these mechanisms. To this end, total RNA from colostrum and mature milk samples were sequenced from 65 sows at differing parities. A stringent bioinformatic pipeline was used to identify and characterize 70,841 transcripts. Results The 70,841 identified transcripts included 42,733 previously annotated transcripts and 28,108 novel transcripts. Differential gene expression analysis was conducted using a generalized linear model coupled with the Lancaster method for P-value aggregation across transcripts. In total, 1667 differentially expressed genes (DEG) were identified for the milk type main effect, and 33 DEG were identified for the milk type x parity interaction. Several gene ontology (GO) terms related to immune response were significant for the milk type main effect, supporting the well-known fact that immunoglobulins and immune cells are transferred to the neonate via colostrum. Conclusions This is the first study to perform global transcriptome analysis from whole milk samples in sows from different parities. Our results provide important information and insight into synthesis of milk proteins and innate immunity and potential targets for future improvement of swine lactation and piglet development.

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