Human heart explant-derived cell extracellular vesicles inhibit NLRP3 inflammasome activation in macrophages
Notice bibliographique
Résumé
Background: Abnormal activation of NLRP3 (NOD-, LRR- and pyrin domain-containing protein 3) inflammasome plays a crucial role in promoting myocardial inflammation and adverse remodeling. Extracellular vesicles (EVs) secreted by heart explant-derived cells (HDCs) have been shown to reduce inflammation and confer cardioprotection in animal models of myocardial infarction. These salutary effects are suggested to be mediated by antiinflammatory microRNA (miRNA) cargo found within the EVs. However, whether HDC EVs can modulate NLRP3 inflammasome activation is not known. Hypothesis & Study Objective: Given their antiinflammatory effects and abundantly enriched miRNA transcripts, we hypothesized that HDC EVs attenuate NLRP3 inflammasome activation. Therefore, the objective of this study was to assess the inhibitory effect of HDC EVs on NLRP3 inflammasome activation in macrophages-a major proinflammatory cell type recruited to myocardium after an ischemic insult. Methods: Human HDCs were cultured from cardiac biopsies in a clinical grade cell manufacturing facility. EVs were isolated from conditioned media (ultracentrifugation) and characterized for their identity (Nanosight & antibody array). Monocytes (THP-1) were differentiated into macrophages with phorbol-myristate acetate (PMA; 3 days) and treated with EVs (4E+10 EVs/mL; 20 hours) before priming (lipopolysaccharide; 4 hours) and activating (nigericin; 1 hour) NLRP3 inflammasome. Caspase-1 activity, IL-1β and IL-18 levels in the culture supernatants were measured using a Caspase-Glo® 1 assay and ELISA respectively. EV miRNA cargo was profiled using nCounter ® human miRNA expression assay. Functional enrichment analysis and miRNA target prediction were performed using bioinformatic tools (Tam 2.0 & miRWalk v3). Results: EV size (160±2 nm) and markers (ICAM, ALIX, CD81, CD63, EPCAM, ANXAS, TSG101, FLOT-1) confirmed EV identity. EV treatment significantly inhibited NLRP3 inflammasome induced caspase-1 activity (67% lower vs. no EV treated, n=4-6, p<0.0001). Further, EV treated macrophages showed a significant reduction in IL-18 (623±8 vs.1462±43 pg/mL, n=3, p=0.0025) and a trend towards reduction in IL-1β levels (1292±115 vs. 2535±115 pg/mL, n=3, p=0.08). MicroRNA set analysis revealed that EVs are enriched with 22 anti-inflammatory miRNAs and importantly 3 of the top 10 significantly enriched functional terms (overrepresentation, p<0.05) are found to be related to immunity and inflammation. Interestingly, EVs are enriched with 4 miRNAs (miR-100, miR-181a, miR-21, miR-22) predicted to inhibit NLRP3 inflammasome. Conclusion: Our findings show that human heart explant-derived cell EVs inhibit activation of NLRP3 inflammasome in macrophages and this effect in part is possibly mediated via transfer of their anti-inflammatory miRNA cargo. These preliminary findings encourage a preclinical investigation to assess EV modulatory effect on NLRP3 inflammasome in models of ischemic heart disease. Canadian Institutes of Health Research Project Grant 410103 (DRD) and University of Ottawa Heart Institute Strategic Research Endowed Fellowship (RV) This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.
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Comment cette classification a été obtenuedéplier
Prédiction distillée sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Apprise à partir de 10 348 étiquettes directes de Codex et de 10 348 étiquettes directes de Gemma. Le mode candidate est l'union des têtes enseignantes seuillées; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont ni des étiquettes humaines ni des étiquettes directes de modèles de pointe.
Scores Codex et Gemma par catégorie
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,000 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule tête enseignante, pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».