PT - JOURNAL ARTICLE AU - Grace Hudson AU - Kyle L. Flannigan AU - Vivek Krishna Pulakazhi Venu AU - Laurie Alston AU - Christina F. Sandall AU - Justin A. MacDonald AU - Daniel A. Muruve AU - Thomas K.H. Chang AU - Sridhar Mani AU - Simon A. Hirota TI - Pregnane X Receptor Activation Triggers Rapid ATP Release in Primed Macrophages That Mediates NLRP3 Inflammasome Activation AID - 10.1124/jpet.118.255679 DP - 2019 Jul 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 44--53 VI - 370 IP - 1 4099 - http://jpet.aspetjournals.org/content/370/1/44.short 4100 - http://jpet.aspetjournals.org/content/370/1/44.full SO - J Pharmacol Exp Ther2019 Jul 01; 370 AB - The pregnane X receptor (PXR) is a ligand-activated nuclear receptor that acts as a xenobiotic sensor, responding to compounds of foreign origin, including pharmaceutical compounds, environmental contaminants, and natural products, to induce transcriptional events that regulate drug detoxification and efflux pathways. As such, the PXR is thought to play a key role in protecting the host from xenobiotic exposure. More recently, the PXR has been reported to regulate the expression of innate immune receptors in the intestine and modulate inflammasome activation in the vasculature. In the current study, we report that activation of the PXR in primed macrophages triggers caspase-1 activation and interleukin-1β release. Mechanistically, we show that this response is nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain-containing 3-dependent and is driven by the rapid efflux of ATP and P2X purinoceptor 7 activation following PXR stimulation, an event that involves pannexin-1 gating, and is sensitive to inhibition of Src-family kinases. Our findings identify a mechanism whereby the PXR drives innate immune signaling, providing a potential link between xenobiotic exposure and the induction of innate inflammatory responses.