Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption
[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
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
Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption
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