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

被引:68
作者
Gianfrancesco, Marco A. [1 ,2 ]
Dehairs, Jonas [3 ]
L'homme, Laurent [4 ]
Herinckx, Gaetan [5 ]
Esser, Nathalie [1 ,2 ]
Jansen, Olivia [6 ]
Habraken, Yvette [7 ]
Lassence, Cedric [7 ]
Swinnen, Johan V. [3 ]
Rider, Mark H. [5 ]
Piette, Jacques [7 ]
Paquot, Nicolas [1 ,2 ]
Legrand-Poels, Sylvie [1 ]
机构
[1] Univ Liege, Lab Immunometab & Nutr, GIGA Inflammat Infect & Immun, Liege, Belgium
[2] Univ Hosp Liege, Dept Med, Div Diabet Nutr & Metab Disorders, Liege, Belgium
[3] Katholieke Univ Leuven, Dept Oncol, Lab Lipid Metab & Canc, Leuven, Belgium
[4] Univ Lille, INSERM, Univ Hosp Lille, Pasteur Inst Lille,U1011,EGID, F-59000 Lille, France
[5] Catholic Univ Louvain, de Duve Inst, B-1200 Brussels, Belgium
[6] Univ Liege, CIRM, Lab Pharmacognosy, Liege, Belgium
[7] Univ Liege, Lab Virol & Immunol, GIGA Mol Biol Dis, Liege, Belgium
来源
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR AND CELL BIOLOGY OF LIPIDS | 2019年 / 1864卷 / 07期
关键词
NLRP3; inflammasome; Obesity; Free fatty acids; Phospholipid; Na; K-ATPase; K+ efflux; INFLAMMASOMES MECHANISM; ENDOPLASMIC-RETICULUM; OXIDATION; INSULIN; OBESITY; ORDER; INFLAMMATION; ERYTHROCYTE; NA; K-ATPASE; INHIBITION;
D O I
10.1016/j.bbalip.2019.04.001
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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-1 beta 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-1 alpha 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 beta-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 CCT alpha, 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.
引用
收藏
页码:1017 / 1030
页数:14
相关论文
共 59 条
[1]   Fatty acid composition of membrane bilayers: Importance of diet polyunsaturated fat balance [J].
Abbott, Sarah K. ;
Else, Paul L. ;
Atkins, Taleitha A. ;
Hulbert, A. J. .
BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES, 2012, 1818 (05) :1309-1317
[2]   Fatty acid composition of skeletal muscle reflects dietary fat composition in humans [J].
Andersson, A ;
Nälsén, C ;
Tengblad, S ;
Vessby, B .
AMERICAN JOURNAL OF CLINICAL NUTRITION, 2002, 76 (06) :1222-1229
[3]   Effects of type 2 diabetes mellitus on plasma fatty acid composition and cholesterol content of erythrocyte and leukocyte membranes [J].
Bakan, E. ;
Yidirim, A. ;
Kurtul, N. ;
Polat, M. F. ;
Dursun, H. ;
Cayir, K. .
ACTA DIABETOLOGICA, 2006, 43 (04) :109-113
[4]   Role of DGAT enzymes in triacylglycerol metabolism [J].
Bhatt-Wessel, Bhumika ;
Jordan, T. William ;
Miller, John H. ;
Peng, Lifeng .
ARCHIVES OF BIOCHEMISTRY AND BIOPHYSICS, 2018, 655 :1-11
[5]   THE RELATION BETWEEN INSULIN SENSITIVITY AND THE FATTY-ACID COMPOSITION OF SKELETAL-MUSCLE PHOSPHOLIPIDS [J].
BORKMAN, M ;
STORLIEN, LH ;
PAN, DA ;
JENKINS, AB ;
CHISHOLM, DJ ;
CAMPBELL, LV .
NEW ENGLAND JOURNAL OF MEDICINE, 1993, 328 (04) :238-244
[6]   Inflammasomes: mechanism of assembly, regulation and signalling [J].
Broz, Petr ;
Dixit, Vishva M. .
NATURE REVIEWS IMMUNOLOGY, 2016, 16 (07) :407-420
[7]   Diacylglycerol Acyltransferase 1 Is Regulated by Its N-Terminal Domain in Response to Allosteric Effectors [J].
Caldo, Kristian Mark P. ;
Acedo, Jeella Z. ;
Panigrahi, Rashmi ;
Vederas, John C. ;
Weselake, Randall J. ;
Lemieux, M. Joanne .
PLANT PHYSIOLOGY, 2017, 175 (02) :667-680
[8]   PtdIns4P on dispersed trans-Golgi network mediates NLRP3 inflammasome activation [J].
Chen, Jueqi ;
Chen, Zhijian J. .
NATURE, 2018, 564 (7734) :71-+
[9]   Western Diet Triggers NLRP3-Dependent Innate Immune Reprogramming [J].
Christ, Anette ;
Guenther, Patrick ;
Lauterbach, Mario A. R. ;
Duewell, Peter ;
Biswas, Debjani ;
Pelka, Karin ;
Scholz, Claus J. ;
Oosting, Marije ;
Haendler, Kristian ;
Bassler, Kevin ;
Klee, Kathrin ;
Schulte-Schrepping, Jonas ;
Ulas, Thomas ;
Moorlag, Simone J. C. F. M. ;
Kumar, Vinod ;
Park, Min Hi ;
Joosten, Leo A. B. ;
Groh, Laszlo A. ;
Riksen, Niels P. ;
Espevik, Terje ;
Schlitzer, Andreas ;
Li, Yang ;
Fitzgerald, Michael L. ;
Netea, Mihai G. ;
Schultze, Joachim L. ;
Latz, Eicke .
CELL, 2018, 172 (1-2) :162-+
[10]   Relationship between plasma insulin and erythrocyte fatty acid composition [J].
Clifton, PM ;
Nestel, PJ .
PROSTAGLANDINS LEUKOTRIENES AND ESSENTIAL FATTY ACIDS, 1998, 59 (03) :191-194