Article (Scientific journals)
Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption
Gianfrancesco, Marco; Dehairs, Jonas; L'homme, Laurent et al.
2019In BBA - Molecular and Cell Biology of Lipids, 1864, p. 1017–1030
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Keywords :
NLRP3 inflammasome; free fatty acids
Abstract :
[en] NLRP3 inflammasome plays a key role in Western diet–induced systemic inflammation and was recently shown to mediate long-lasting trained immunity in myeloid cells. Saturated fatty acids (SFAs) are sterile triggers able to induce the assembly of the NLRP3 inflammasome in macrophages, leading to IL-1β secretion while unsaturated ones (UFAs) prevent SFAs-mediated NLRP3 activation. Unlike previous studies using LPS-primed bone marrow derived macrophages, we do not see any ROS or IRE-1α involvement in SFAs-mediated NLRP3 activation in human monocytes-derived macrophages. Rather we show that SFAs need to enter the cells and to be activated into acyl-CoA to lead to NLRP3 activation in human macrophages. However, their β-oxidation is dispensable. Instead, they are channeled towards phospholipids but redirected towards lipid droplets containing triacylglycerol in the presence of UFAs. Lipidomic analyses and Laurdan fluorescence experiments demonstrate that SFAs induce a dramatic saturation of phosphatidylcholine (PC) correlated with a loss of membrane fluidity, both events inhibited by UFAs. The silencing of CCTα, the key enzyme in PC synthesis, prevents SFA-mediated NLRP3 activation, demonstrating the essential role of the de novo PC synthesis. This SFA-induced membrane remodeling promotes a disruption of the plasma membrane Na, K-ATPase, instigating a K+ efflux essential and sufficient for NLRP3 activation. This work opens novel therapeutic avenues to interfere with Western diet-associated diseases such as those targeting the glycerolipid pathway.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Gianfrancesco, Marco ;  Université de Liège - ULiège > Département des sciences fonctionnelles (DSF) > Biochimie et biologie moléculaire
Dehairs, Jonas;  KU Leuven > Department of Oncology > Laboratory of Lipid Metabolism and Cancer
L'homme, Laurent;  University of Lille, Inserm, University Hospital of Lille, Pasteur Institute of Lille
Herinckxe, Gaëtan;  Catholic University of Louvain - UCL > de Duve Institute
Esser, Nathalie;  Université de Liège - ULiège > GIGA-Inflammation, Infection & Immunity
Jansen, Olivia ;  Université de Liège - ULiège > Département de pharmacie > Pharmacognosie
Habraken, Yvette ;  Université de Liège - ULiège > Molecular Biology of Diseases-Gene Expression & Cancer
Lassence, Cédric ;  Université de Liège - ULiège > Département des sciences de la vie > Département des sciences de la vie
Swinnen, Johan;  KU Leuven > Department of Oncology > Laboratory of Lipid Metabolism and Cancer
Rider, Mark;  Université Catholique de Louvain - UCL > de Duve Institute
Piette, Jacques ;  Université de Liège - ULiège > I3-Virology and Immunology
PAQUOT, Nicolas ;  Centre Hospitalier Universitaire de Liège - CHU > Département de médecine interne > Service de diabétologie, nutrition, maladies métaboliques
Legrand, Sylvie ;  Université de Liège - ULiège > I3-Immunometabolism and Nutrition
More authors (3 more) Less
Language :
English
Title :
Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption
Publication date :
April 2019
Journal title :
BBA - Molecular and Cell Biology of Lipids
ISSN :
1388-1981
Volume :
1864
Pages :
1017–1030
Peer reviewed :
Peer reviewed
Available on ORBi :
since 16 April 2019

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