Activation Of The Constitutive Androstane Receptor Enhances Wound Healing – A New Link Between Xenobiotic Sensing And Intestinal Mucosal Homeostasis?
Notice bibliographique
Résumé
Background Compounds released from the intestinal microbiota may play a role in maintaining mucosal homeostasis, but little is known about the receptors that sense and respond to these compounds. Recently a cytosolic xenobiotic sensor, called the pregnane X receptor (PXR), was identified as a receptor for microbial metabolites, and shown to play a key role in regulating intestinal epithelial barrier and wound healing following injury. In the current study, we sought to determine whether the constitutive androstane receptor (CAR), which shares structural, functional and pharmacological features with the PXR, plays a role in regulating wound healing and mucosal repair. Methods Caco‐2 intestinal epithelial cells were used to model wound healing. Wounds formed using Ibidi culture inserts were treated with CITCO, a selective human CAR agonist, and imaged for 24 hours. Wound closure was quantified and cell migration tracks assessed. To interrogate the intracellular events involved in the CITCO‐induced responses, we assessed the role of p38 MAPK and ERK1/2 signaling in our assays, along with proliferation and migration (xCELLigence impedance‐based migration assay). To determine the role of the CAR in vivo , we assessed recovery from dextran sulphate sodium (DSS)‐induced colitis (2.5% W/V in drinking water; 5 days exposure, followed by 9 days of recovery) in CAR‐deficient mice and WT mice treated with TCPOBOP (3 mg/kg; IP; daily during recovery phase), a selective rodent CAR agonist. Results Activation of the CAR enhanced wound closure in Caco‐2 monolayers, which was associated with increased cell migration, but not proliferation. The enhancement of cell migration was dependent on p38 MAPK signaling. Treating WT mice with a CAR agonist accelerated their recovery from DSS‐induced colitis. In contrast, CAR‐deficient mice exhibited delayed recovery. Conclusions Our data suggest that the CAR regulates the cellular events that contribute to wound healing and mucosal restitution following injury. While the microbe‐derived compounds that activate the CAR have yet to be identified, its close relative, the PXR, has been shown to respond to such ligands. Taken together, we posit that xenobiotic receptors play a key role in regulating the response to injury and may provide new therapeutic targets to enhance mucosal repair. Support or Funding Information Crohn's & Colitis Canada; Canadian Foundation for Innovation; The Dr. Lloyd Sutherland Investigatorship in IBD/GI Research
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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 ».