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

J Exp Med. 2019 Dec 2;216(12):2838-2853. doi: 10.1084/jem.20190111. Epub 2019 Sep 26.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Calcium / metabolism
  • Caspase 1 / metabolism
  • Furans / pharmacology
  • Heterocyclic Compounds, 4 or More Rings
  • Humans
  • Inflammasomes / metabolism*
  • Interleukin-18 / metabolism
  • Interleukin-1beta / metabolism
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Mice
  • NIMA-Related Kinases / metabolism*
  • NLR Family, Pyrin Domain-Containing 3 Protein / antagonists & inhibitors
  • NLR Family, Pyrin Domain-Containing 3 Protein / metabolism*
  • Phosphate-Binding Proteins / metabolism
  • Platelet Activating Factor / metabolism*
  • Platelet Membrane Glycoproteins / metabolism*
  • Potassium / metabolism
  • Receptors, G-Protein-Coupled / metabolism*
  • Sulfonamides / pharmacology
  • Sulfones

Substances

  • Furans
  • Gsdmd protein, mouse
  • Heterocyclic Compounds, 4 or More Rings
  • Inflammasomes
  • Interleukin-18
  • Interleukin-1beta
  • Intracellular Signaling Peptides and Proteins
  • MCC-950
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Phosphate-Binding Proteins
  • Platelet Activating Factor
  • Platelet Membrane Glycoproteins
  • Receptors, G-Protein-Coupled
  • Sulfonamides
  • Sulfones
  • platelet activating factor receptor
  • NIMA-Related Kinases
  • Nek7 protein, mouse
  • Caspase 1
  • Potassium
  • Calcium