Fiche publication
Date publication
mai 2013
Auteurs
Membres identifiés du Cancéropôle Est :
Pr CHAMBON Pierre
Tous les auteurs :
Mukherji A, Kobiita A, Ye T, Chambon P
Lien Pubmed
Résumé
Alterations of symbiosis between microbiota and intestinal epithelial cells (IEC) are associated with intestinal and systemic pathologies. Interactions between bacterial products (MAMPs) and Toll-like receptors (TLRs) are known to be mandatory for IEC homeostasis, but how TLRs may time homeostatic functions with circadian changes is unknown. Our functional and molecular dissections of the IEC circadian clock demonstrate that its integrity is required for microbiota-IEC dialog. In IEC, the antiphasic expression of the RORalpha activator and RevErbalpha repressor clock output regulators generates a circadian rhythmic TLR expression that converts the temporally arrhythmic microbiota signaling into circadian rhythmic JNK and IKKbeta activities, which prevents RevErbalpha activation by PPARalpha that would disrupt the circadian clock. Moreover, through activation of AP1 and NF-kappaB, these activities, together with RORalpha and RevErbalpha, enable timing homeostatic functions of numerous genes with IEC circadian events. Interestingly, microbiota signaling deficiencies induce a prediabetic syndrome due to ileal corticosterone overproduction consequent to clock disruption.
Référence
Cell. 2013 May 9;153(4):812-27
