Apoptotic endothelial cells release small extracellular vesicles loaded with immunostimulatory viral-like RNAs
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ABSTRACT:
PROVIDER: PRJNA488132 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR7759980_1.fastq.gz | Fastqsanger.gz | |||
| SRR7759980_2.fastq.gz | Fastqsanger.gz | |||
| SRR7759981.fastq.gz | Fastqsanger.gz | |||
| SRR7759982_1.fastq.gz | Fastqsanger.gz | |||
| SRR7759982_2.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: Compare the RNA content of apoptotic human umbilical vein endothelial cells (HUVECs)-released vesicles: 1) Apoptotics bodies and 2) Apoptotic Exo-like vesicles, which are immunogenic and promote autoimmunity. Results: The transcriptome of ApoExos was unique with regards to its genomic origin, nucleotide composition and secondary structure. We show that ApoExos essentially contain non-ribosomal non-coding RNAs, among which 89% are derived from viral-like endogenous retroelements (EREs). ApoExos are also enriched in U-rich linear nucleotide sequences and Alus repeats. Conclusion: Our work demonstrates that apoptotic endothelial cells release EVs loaded with RNAs recognized by RLRs and endosomal TLRs (TLR3, TLR7 and TLR8), and are therefore tailor-made for initiation of innate immune responses and autoimmunity.
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Project description:Endothelial cells have multifaceted interactions with the immune system, both as initiators and targets of immune responses. In vivo, apoptotic endothelial cells release two types of extracellular vesicles upon caspase-3 activation: apoptotic bodies and exosome-like nanovesicles (ApoExos). Only ApoExos are immunogenic: their injection causes inflammation and autoimmunity in mice. Based on deep sequencing of total RNA, we report that apoptotic bodies and ApoExos are loaded with divergent RNA cargos that are not released by healthy endothelial cells. Apoptotic bodies, like endothelial cells, contain mainly ribosomal RNA whereas ApoExos essentially contain non-ribosomal non-coding RNAs. Endogenous retroelements, bearing viral-like features, represented half of total ApoExos RNA content. ApoExos also contained several copies of unedited Alu repeats and large amounts of non-coding RNAs with a demonstrated role in autoimmunity such as U1 RNA and Y RNA. Moreover, ApoExos RNAs had a unique nucleotide composition and secondary structure characterized by strong enrichment in U-rich motifs and unstably folded RNAs. Globally, ApoExos were therefore loaded with RNAs that can stimulate a variety of RIG-I-like receptors and endosomal TLRs. Hence, apoptotic endothelial cells selectively sort in ApoExos a diversified repertoire of immunostimulatory "self RNAs" that are tailor-made for initiation of innate immune responses and autoimmunity.
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Project description:RNA was harvested from RAW 264.7 cells treated with miR-loaded extracellular vesicles
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Project description:Persistent endothelial injury promotes maladaptive responses by favoring the release of factors leading to perturbation in vascular homeostasis and tissue architecture. Caspase-3 dependent death of microvascular endothelial cells leads to the release of unique apoptotic exosome-like vesicles (ApoExo). Here, we evaluate the impact of ApoExo on endothelial gene expression and function in the context of a pro-apoptotic stimulus. Endothelial cells exposed to ApoExo differentially express genes involved in cell death, inflammation, differentiation, and cell movement. Endothelial cells exposed to ApoExo showed inhibition of apoptosis, improved wound closure along with reduced angiogenic activity and reduced expression of endothelial markers consistent with the first phase of endothelial-to-mesenchymal transition (endoMT). ApoExo interaction with endothelial cells also led to NF-κB activation. NF-κB is known to participate in endothelial dysfunction in numerous diseases. Silencing NF-κB reversed the anti-apoptotic effect and the pro-migratory state and prevented angiostatic properties and CD31 downregulation in endothelial cells exposed to ApoExo. This study identifies vascular injury-derived extracellular vesicles (ApoExo) as novel drivers of NF-κB activation in endothelial cells and demonstrates the pivotal role of this signaling pathway in coordinating ApoExo-induced functional changes in endothelial cells. Hence, targeting ApoExo-mediated NF-κB activation in endothelial cells opens new avenues to prevent endothelial dysfunction.
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Project description:Systemic administration of interleukin (IL)-12 has been shown to induce potent anti-tumor immune responses in preclinical cancer models. Previous clinical trials using bolus IL-12 injection through maximal tolerable dosing (MTD) strategies indicated limited efficacy alongside unwanted side-effects. Our group developed IL-12-loaded PLGA nanospheres (IL12ns) that release their contents systemically in a slow, controlled manner. An immune diagnostic platform (IDP), capable of monitoring therapeutic response through peripheral blood sampling, was designed alongside this immunostimulatory therapy. The systemic immune responses from MTD and IL12ns dosing strategies were analyzed using this IDP in healthy mice. Importantly, the MTD was associated with aberrant peripheral immune stimulation, evidenced by increased IL-12, interferon gamma (IFNG), and IL-10 signaling. The immune-protective effects of IL12ns were supported by increases in pro-inflammatory plasma cytokines/chemokines without the maladaptive transcriptomic signatures in circulating peripheral immune cells. These data ultimately support the necessity of a vector system for safe immunostimulatory IL-12 therapy.
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Project description:Apoptosis accounts for ~ 90% of homeostatic cell turnover in the body1. While caspase-dependent apoptosis is known to influence immune tolerance, induction of cell proliferation, and tissue regeneration2-4, how these apoptotic cells contribute to such diverse effects is less understood. Soluble factors released from apoptotic cells could be a means of ‘talking’ to healthy cells in the tissue neighborhood. While a few phagocyte-attracting ‘find-me’ signals released from apoptotic cells are known5, the larger ‘metabolite secretome’ from apoptotic cells is not yet defined. Here, via unbiased profiling of the apoptotic cell secretome, we identified 123 metabolites that are specifically released during apoptosis, while cells still retain membrane integrity. Release of ~25 of these metabolites is dependent on Pannexin 1 (Panx1) channels, which are opened by caspase-dependent cleavage during apoptosis. Interestingly, one of the Panx1-dependent metabolites from apoptotic cells is spermidine, a polyamine whose release could be, in part, due to the continued metabolic activity of dying cells. RNAseq analysis of healthy cells exposed to the apoptotic secretome revealed Panx1-dependent gene programs, including genes linked to suppression of inflammation, cell proliferation, and wound healing. Analysis of the apoptotic secretome across cell types and different apoptotic stimuli, identified a core “set” of 8 Panx1-dependent metabolites. Strikingly, a selected cocktail of these metabolites demonstrated significant immunosuppressive effects by potently reducing disease severity in an inflammatory arthritis model and a lung graft rejection model. Collectively, these data advance the concept that apoptotic cells are not ‘inert’ corpses waiting for removal by phagocytes, but rather they actively communicate with the tissue environment through their metabolite secretome, with implications in tissue inflammation.
2020-03-19 | GSE131906 | GEO
Project description:Apoptotic cells actively release metabolite messanger with anti-inflammatory properties
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Project description:he dynamic balance of hypoxia and oxidative stress constitutes the oxygen-related microenvironment in injured tissues. Oxygen homeostasis is highly variable; therefore, it is not a therapeutic target for injured tissue repair. We found an enrichment and extensive apoptosis of mesenchymal stem cells (MSCs) infused intravenously in the wound microenvironment with co-existing hypoxia and oxidative stress. Apoptotic bodies (ABs), generated from in situ apoptosis, significantly promotes angiogenesis. We improved the derivation pathway of ABs by simulating oxygen homeostasis in injured tissues, with cobalt chloride-induced hypoxia or hydrogen peroxide-induced oxidative stress in MSCs. Oxygen-related environmental stressed ABs, derived from environments of hypoxic and oxidative stress, were identified and loaded onto hydrogel microspheres for accurate regulation of endothelial cells (ECs) vascularization. These ABs directly targeted ECs; oxidative stress ABs (Oxi-ABs) have a 2.5- and 4-fold higher tube-forming ability than hypoxic and normoxic ABs, respectively. miRNA microarray analysis revealed that different oxygen-stressed ABs deliver similar miRNAs, which leads to the broad upregulation of EC phosphokinase activity. Finally, local delivery of Oxi-ABs-loaded hydrogel microspheres promotes wound healing. Oxi-ABs-loaded hydrogel microspheres achieved controlled AB release, targeting EC by reducing the consumption of early inflammatory cells and adapting to the proliferative phase of wound healing. Thus, the biogenerated apoptotic bodies responding to oxygen-related environmental stress can target ECs to promote vascularization.
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