Rôle de la NTPDase8 et du récepteur P2Y6 dans l'inflammation intestinale
|Abstract:||Inflammatory bowel diseases (IBD) are characterized by a dysfunction of the intestinal epithelium and a dysregulation of the immune system balance. The inflammation underlying IBD could be triggered and/or exacerbated by danger signals such as nucleotides. The nucleotides activate P2 receptors and their level is modulated by ectonucleotidases which include members of the ectonucleoside triphosphate diphosphohydrolases (E-NTPDases) family. We identified the last member of this family of enzymes, the NTPDase8. We originally found its expression in the intestine at the RNA level. In this work, we demonstrate that NTPDase8 is expressed at the apical surface of intestinal epithelial cells (IEC) in the colon. Our results indicate that NTPDase8 is a key protector of intestinal inflammation by regulating the activation of P2Y6 receptor as the administration of the enzyme protects totally from the intestinal inflammation. In agreement, the deletion of NTPDase8 gene leads to a dramatic increase of inflammation is a murine model of colitis. The second aspect addressed in my thesis is the regulatory role of the P2Y6 receptor in intestinal inflammation. We found that this receptor expressed on IEC is pro-inflammatory and that blocking it pharmacologically prevented the intestinal inflammation triggered in a colitis model. We have also demonstrated that the P2Y6 receptor plays a key role in regulating the activity of other nucleotide receptors in vitro, which influences the homeostasis of intestinal epithelial cells. Our work deciphers the importance of nucleotide signaling in the pathogenesis of experimental colitis and highlights properties that could be applied to other gastrointestinal disorders. In extension, these data suggest that NTPDase8-P2Y6 axis could be a therapeutic target in the treatment of IBD.|
|Document Type:||Thèse de doctorat|
|Open Access Date:||9 November 2019|
|Collection:||Thèses et mémoires|
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