Pregnane X Receptor (PXR) modulates NLRP3 Inflammasome

Abstract

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, 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.