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

Gianfrancesco, Marco A.;Dehairs, Jonas;L'homme, Laurent;Herinckx, Gaëtan;Legrand-Poels, Sylvie;et.al.
(2019) Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids — Vol. 1864, n° 7, p. 1017-1030 (2019)

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Authors
  • Gianfrancesco, Marco A.University of Liège
    Author
  • Dehairs, JonasKU Leuven
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  • L'homme, LaurentUniversity of Lille
    Author
  • Herinckx, GaëtanUCLouvain
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  • Rider, Mark H.UCLouvain
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  • Legrand-Poels, SylvieUniversity of Liège
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Abstract
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 triacylgly- cerol 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.
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Gianfrancesco, M. A., Dehairs, J., L’homme, L., Herinckx, G., Esser, N., Jansen, O., Habraken, Y., Lassence, C., Swinnen, J. V., Rider, M. H., Piette, J., Paquot, N., & Legrand-Poels, S. (2019). Saturated fatty acids induce NLRP3 activation in human macrophages through K+ efflux resulting from phospholipid saturation and Na, K-ATPase disruption. Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids, 1864(7), 1017-1030. https://doi.org/10.1016/j.bbalip.2019.04.001 (Original work published 2019)