title: Saturated Fatty Acids Engage an IRE1α-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells.
abstract: Diets rich in saturated fatty acids (SFAs) produce a form of tissue inflammation driven by "metabolically activated" macrophages. We show that SFAs, when in excess, induce a unique transcriptional signature in both mouse and human macrophages that is enriched by a subset of ER stress markers, particularly IRE1α and many adaptive downstream target genes. SFAs also activate the NLRP3 inflammasome in macrophages, resulting in IL-1β secretion. We found that IRE1α mediates SFA-induced IL-1β secretion by macrophages and that its activation by SFAs does not rely on unfolded protein sensing. We show instead that the ability of SFAs to stimulate either IRE1α activation or IL-1β secretion can be specifically reduced by preventing their flux into phosphatidylcholine (PC) or by increasing unsaturated PC levels. Thus, IRE1α is an unrecognized intracellular PC sensor critical to the process by which SFAs stimulate macrophages to secrete IL-1β, a driver of diet-induced tissue inflammation.
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Megan M
authors.initials: MM
authors.lastname: Robblee
authors.affiliation: Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Charles C
authors.initials: CC
authors.lastname: Kim
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Jess
authors.initials: J
authors.lastname: Porter Abate
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Valdearcos
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Karin L M
authors.initials: KL
authors.lastname: Sandlund
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA.
authors.forename: Meera K
authors.initials: MK
authors.lastname: Shenoy
authors.affiliation: Universite de Toulouse, INP, ENVT, UMR1225, IHAP, 31076 Toulouse, France; INRA, UMR1225, IHAP, 31076 Toulouse, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Volmer
authors.affiliation: Education and Research Support Center, Graduate School of Medicine, Gunma University, Maebashi, Gunma 371-8511, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Iwawaki
authors.affiliation: Diabetes Center, University of California San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California San Francisco, San Francisco, CA 94143, USA; Department of Medicine, University of California San Francisco, San Francisco, CA 94143, USA. Electronic address: skoliwad@diabetes.ucsf.edu.
authors.forename: Suneil K
authors.initials: SK
authors.lastname: Koliwad
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002478:Cells, Cultured; D004032:Diet; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology*; D006801:Humans; D058847:Inflammasomes / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D008070:Lipopolysaccharides / Q000633:toxicity; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein / Q000378:metabolism*; D010713:Phosphatidylcholines / Q000378:metabolism; D025341:Principal Component Analysis; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D000071717:X-Box Binding Protein 1 / Q000235:genetics / Q000378:metabolism
chemical_list: D005227:Fatty Acids; D058847:Inflammasomes; D053583:Interleukin-1beta; D008070:Lipopolysaccharides; D000071199:NLR Family, Pyrin Domain-Containing 3 Protein; D010713:Phosphatidylcholines; D000071717:X-Box Binding Protein 1; C000605544:Xbp1 protein, mouse; C510185:Ern1 protein, mouse; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases