Pregnane X Receptor (PXR) modulates NLRP3 Inflammasome

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dc.contributor.advisorHirota, Simon
dc.contributor.authorHudson, Grace
dc.contributor.committeememberMcCafferty, Donna-Marie
dc.contributor.committeememberChadee, Khrisendath
dc.date2018-02
dc.date.accessioned2018-01-19T00:55:56Z
dc.date.available2018-01-19T00:55:56Z
dc.date.issued2017-12-18
dc.description.abstractCompounds 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, the pregnane X receptor (PXR), was identified as a receptor for microbial metabolites in the gastrointestinal (GI) tract. The PXR has been shown to play a protective role in the gut, with gene variants associated with IBD risk. Recent data suggest that the PXR may regulate innate immune signaling platforms, in a variety of tissues. In vascular endothelial cells, the PXR was shown to stimulate the expression of NLRP3, and initiate NLRP3 inflammasome activation. Interestingly, alterations in NLRP3 inflammasome function have been linked to IBD susceptibility. In the current thesis, we sought to characterize the role of the PXR in modulating the function of the NLRP3 inflammasome in macrophages, a key innate immune cell that contributes to host-defense and the regulation of intestinal mucosal homeostasis. Using the THP-1 cell line and mouse peritoneal macrophages, we found that PXR agonists stimulated caspase-1 activation, along with IL-1β processing and release. These responses were lost in cells lacking NLRP3 and blocked by selective inhibition of caspase-1. Furthermore, PXR-deficient cells failed to activate caspase-1 and release IL-1β in response to PXR agonist stimulation. Lastly, we found that PXR activation triggered ATP release, an effect that was responsible for inflammasome activation, as these responses were abolished by apyrase and P2X7 inhibition. Through this thesis, we demonstrated that the PXR activates the NLRP3 inflammasome through stimulating ATP release within a macrophage.en_US
dc.identifier.citationHudson, G.M. (2017). Pregnane X Receptor (PXR) modulates NLRP3 Inflammasome (Master's thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.en_US
dc.identifier.doihttp://dx.doi.org/10.11575/PRISM/5362
dc.identifier.urihttp://hdl.handle.net/1880/106281
dc.language.isoenen_US
dc.publisher.facultyCumming School of Medicineen_US
dc.publisher.institutionUniversity of Calgaryen
dc.rightsUniversity of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.en_US
dc.subjectNLRP3 Inflammasomeen_US
dc.subjectxenobiotic receptorsen_US
dc.subject.classificationPhysiologyen_US
dc.subject.classificationImmunologyen_US
dc.subject.classificationPathologyen_US
dc.subject.classificationPharmacologyen_US
dc.titlePregnane X Receptor (PXR) modulates NLRP3 Inflammasomeen_US
dc.typemaster thesisen_US
thesis.degree.disciplineMedicine – Gastrointestinal Sciencesen_US
thesis.degree.grantorUniversity of Calgaryen_US
thesis.degree.nameMaster of Science (MSc)en_US
ucalgary.item.requestcopytrue
ucalgary.thesis.checklistI confirm that I have submitted all of the required forms to Faculty of Graduate Studies.en_US
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