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Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR
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 th...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Rockefeller University Press
2019
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888982/ https://www.ncbi.nlm.nih.gov/pubmed/31558613 http://dx.doi.org/10.1084/jem.20190111 |
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author | Deng, Meng Guo, Haitao Tam, Jason W. Johnson, Brandon M. Brickey, W. June New, James S. Lenox, Austin Shi, Hexin Golenbock, Douglas T. Koller, Beverly H. McKinnon, Karen P. Beutler, Bruce Ting, Jenny P.-Y. |
author_facet | Deng, Meng Guo, Haitao Tam, Jason W. Johnson, Brandon M. Brickey, W. June New, James S. Lenox, Austin Shi, Hexin Golenbock, Douglas T. Koller, Beverly H. McKinnon, Karen P. Beutler, Bruce Ting, Jenny P.-Y. |
author_sort | Deng, Meng |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-6888982 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Rockefeller University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-68889822020-06-02 Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR Deng, Meng Guo, Haitao Tam, Jason W. Johnson, Brandon M. Brickey, W. June New, James S. Lenox, Austin Shi, Hexin Golenbock, Douglas T. Koller, Beverly H. McKinnon, Karen P. Beutler, Bruce Ting, Jenny P.-Y. J Exp Med Research Articles 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. Rockefeller University Press 2019-12-02 2019-10-26 /pmc/articles/PMC6888982/ /pubmed/31558613 http://dx.doi.org/10.1084/jem.20190111 Text en © 2019 Deng et al. http://www.rupress.org/terms/https://creativecommons.org/licenses/by-nc-sa/4.0/This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/). |
spellingShingle | Research Articles Deng, Meng Guo, Haitao Tam, Jason W. Johnson, Brandon M. Brickey, W. June New, James S. Lenox, Austin Shi, Hexin Golenbock, Douglas T. Koller, Beverly H. McKinnon, Karen P. Beutler, Bruce Ting, Jenny P.-Y. Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR |
title | Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR |
title_full | Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR |
title_fullStr | Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR |
title_full_unstemmed | Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR |
title_short | Platelet-activating factor (PAF) mediates NLRP3-NEK7 inflammasome induction independently of PAFR |
title_sort | platelet-activating factor (paf) mediates nlrp3-nek7 inflammasome induction independently of pafr |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888982/ https://www.ncbi.nlm.nih.gov/pubmed/31558613 http://dx.doi.org/10.1084/jem.20190111 |
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