Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR

Meng Deng, Haitao Guo, Jason W. Tam, Brandon M. Johnson, W. June Brickey, James S. New, Austin Lenox, Hexin Shi, Douglas T. Golenbock, Beverly H. Koller, Karen P. McKinnon, Bruce Beutler, Jenny P.Y. Ting

Research output: Contribution to journalArticle

8 Scopus citations

Abstract

The role of lipids in inflammasome activation remains underappreciated. The phospholipid, platelet-activating factor (PAF), exerts multiple physiological functions by binding to a G protein-coupled seven-transmembrane receptor (PAFR). PAF is associated with a number of inflammatory disorders, yet the molecular mechanism underlying its proinflammatory function remains to be fully elucidated. We show that multiple PAF isoforms and PAF-like lipids can activate the inflammasome, resulting in IL-1β and IL-18 maturation. This is dependent on NLRP3, ASC, caspase-1, and NEK7, but not on NLRC4, NLRP1, NLRP6, AIM2, caspase-11, or GSDMD. Inflammasome activation by PAF also requires potassium efflux and calcium influx but not lysosomal cathepsin or mitochondrial reactive oxygen species. PAF exacerbates peritonitis partly through inflammasome activation, but PAFR is dispensable for PAF-induced inflammasome activation in vivo or in vitro. These findings reveal that PAF represents a damage-associated signal that activates the canonical inflammasome independently of PAFR and provides an explanation for the ineffectiveness of PAFR antagonist in blocking PAF-mediated inflammation in the clinic.

Original languageEnglish (US)
Pages (from-to)2838-2853
Number of pages16
JournalJournal of Experimental Medicine
Volume216
Issue number12
DOIs
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Deng, M., Guo, H., Tam, J. W., Johnson, B. M., Brickey, W. J., New, J. S., Lenox, A., Shi, H., Golenbock, D. T., Koller, B. H., McKinnon, K. P., Beutler, B., & Ting, J. P. Y. (2019). Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR. Journal of Experimental Medicine, 216(12), 2838-2853. https://doi.org/10.1084/jem.20190111