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

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

Author information

1
Oral and Craniofacial Biomedicine PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC.
2
Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC.
3
Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC.
4
Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
5
Department of Microbiology, University of Alabama at Birmingham, Birmingham, AL.
6
Center for the Genetics of Host Defense, University of Texas Southwestern Medical Center, Dallas, TX.
7
Division of Infectious Diseases and Immunology, University of Massachusetts Medical School, Worcester, MA.
8
Oral and Craniofacial Biomedicine PhD Program, University of North Carolina at Chapel Hill, Chapel Hill, NC jenny_ting@med.unc.edu.

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.

PMID:
31558613
DOI:
10.1084/jem.20190111

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