Pregnane X receptor activation triggers rapid ATP release in primed macrophages that mediates NLRP3 inflammasome activation

Grace Hudson, Kyle L. Flannigan, Vivek Krishna Pulakazhi Venu, Laurie Alston, Christina F. Sandall, Justin A. MacDonald, Daniel A. Muruve, Thomas K.H. Chang, Sridhar Mani, Simon A. Hirota

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Abstract

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-1b 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.

Original languageEnglish (US)
Pages (from-to)44-53
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume370
Issue number1
DOIs
StatePublished - Jan 1 2019

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Hudson, G., Flannigan, K. L., Venu, V. K. P., Alston, L., Sandall, C. F., MacDonald, J. A., Muruve, D. A., Chang, T. K. H., Mani, S., & Hirota, S. A. (2019). Pregnane X receptor activation triggers rapid ATP release in primed macrophages that mediates NLRP3 inflammasome activation. Journal of Pharmacology and Experimental Therapeutics, 370(1), 44-53. https://doi.org/10.1124/jpet.118.255679