TY - JOUR
T1 - Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR
AU - Deng, Meng
AU - Guo, Haitao
AU - Tam, Jason W.
AU - Johnson, Brandon M.
AU - Brickey, W. June
AU - New, James S.
AU - Lenox, Austin
AU - Shi, Hexin
AU - Golenbock, Douglas T.
AU - Koller, Beverly H.
AU - McKinnon, Karen P.
AU - Beutler, Bruce
AU - Ting, Jenny P.Y.
N1 - Funding Information:
We sincerely thank Dr. Takao Shimizu (University of Tokyo, Tokyo, Japan) for approval to use the Pafr-/- mice, Dr. John F. Kearney (University of Alabama at Birmingham, Birmingham, AL) for providing Pafr-/- mice, and Dr. Russell Vance (University of California, Berkeley, Berkeley, CA) for approval and Dr. Edward Miao (University of North Carolina Chapel Hill, Chapel Hill, NC) for sharing Gsdmd-/- mice. This work was supported by National Institutes of Health grants R01 AI029564, R01 CA156330, R35 CA232109, and P01 DK094779 to J.P.-Y. Ting; AI14782 and U01 AI100005 to Dr. John F. Kearney (University of Alabama at Birmingham); and A1007051 to J.S. New. The University of North Carolina Flow Cytometry Core Facility and Microscopy Services Laboratory is supported by the National Institutes of Health P30 CA016086 Cancer Center Core Support Grant to the University of North Carolina Lineberger Comprehensive Cancer Center. The authors declare no competing financial interests.
Funding Information:
This work was supported by National Institutes of Health grants R01 AI029564, R01 CA156330, R35 CA232109, and P01 DK094779 to J.P.-Y. Ting; AI14782 and U01 AI100005 to Dr. John F. Kearney (University of Alabama at Birmingham); and A1007051 to J.S. New. The University of North Carolina Flow Cytometry Core Facility and Microscopy Services Laboratory is supported by the National Institutes of Health P30 CA016086 Cancer Center Core Support Grant to the University of North Carolina Lineberger Comprehensive Cancer Center. The authors declare no competing financial interests.
Publisher Copyright:
© 2019 Deng et al.
PY - 2019/12/1
Y1 - 2019/12/1
N2 - 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.
AB - 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.
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U2 - 10.1084/jem.20190111
DO - 10.1084/jem.20190111
M3 - Article
C2 - 31558613
AN - SCOPUS:85075170856
SN - 0022-1007
VL - 216
SP - 2838
EP - 2853
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 12
ER -