Tafazzin contributes to IgE‐mediated mast cell degranulation and cytokine secretion
Notice bibliographique
Résumé
Prevalence of allergic pathologies, such as food allergies, asthma, and atopic dermatitis, have been on the rise over the past several decades with approximately 40% of children in developed nations suffering one of these chronic inflammatory diseases. These pathologies, driven largely by sentinel immune cells known as mast cells, occur in tissues that interface with the external environment. Induction of the allergic response is initiated through the activation of FceRI by receptor‐bound allergen‐specific IgE. Subsequently, mast cells rapidly modulate various metabolic pathways to meet the energy demands associated with the processes directing both the early and late phases of the allergic response. The growing field of immunometabolism suggests that immune cell function can be modulated through effective regulation of metabolic processes. The purpose of this study was to assess the role of tafazzin, a mitochondrial cardiolipin remodeler, in modulating FceRI‐mediated mast cell activation. Primary mast cell cultures were established using fetal livers generated through breeding of heterozygotes carrying the doxycycline‐inducible TAZ shRNA knockdown cassette. Hematopoietic progenitors from homozygote and wild‐type fetal liver, were differentiated into mature mast cells under the direction of IL‐3, PGE 2 , and stem cell factor. TAZ knockdown was initiated by 1 μg/ml doxycycline (dox) for 5 days, resulting in a 99.9% reduction in tafazzin protein content relative to baseline expression and a 99.7% reduction relative to wild‐type control. Flow cytometric analysis of mast cell receptor expression demonstrated that FcɛRI was unimpacted by dox treatment, allowing for interrogation of induced signaling‐mediated responses. Following tafazzin knockdown, anti‐TNP IgE‐sensitized liver‐derived mast cells (LMC) were assessed in b‐hexosaminidase degranulation assays identifying a 31.4% reduction in degranulation (n = 4, p < 0.05) between the TAZ shRNA +/+ cells and the wild‐type LMCs activated with TNP‐BSA (allergen) with SCF potentiation. ELISA (n = 6) were conducted to analyze the secretion of de novo synthesized inflammatory mediators. TAZ shRNA +/+ cells secreted lower levels of CCL1 (p < 0.01), CCL2 (p < 0.05), and TNF (p < 0.001) when compared to wild‐type cells treated with dox. Induced transcription was analyzed using qPCR (n = 4) to assess if differences detected in mediator secretion were due to altered transcription. Transcript levels following a knockdown in tafazzin protein levels were significantly reduced at the 60‐minute timepoint for CCL1 (p < 0.05); while other genes analyzed, such as CCL2 and TNF , were not significantly impacted. These results suggest that tafazzin contributes to FceRI‐mediated mast cell secretory mechanisms in both the early (degranulation) and late phases (secretion of de novo synthesized mediators) of the allergic response. Collectively, this work supports the notion that regulation of mast cell metabolism is a potentially viable approach for ameliorating the severity of mast cell‐mediated pathologies. Support or Funding Information Supported by the Natural Sciences and Engineering Research Council of Canada (NSERC); Canada Foundation for Innovation (CFI); Government of Ontario; and, Brock University.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| 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) | 0,001 | 0,001 |
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 source (Gemma direct ou Codex distillé), 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 ».