Saturated Fatty Acids Engage an IRE1α-Dependent Pathway to Activate the NLRP3 Inflammasome in Myeloid Cells

• Published in: Cell reports (Cambridge) Vol. 14; no. 11; pp. 2611 - 2623
• Main Authors: Robblee, Megan M., Kim, Charles C., Abate, Jess Porter, Valdearcos, Martin, Sandlund, Karin L.M., Shenoy, Meera K., Volmer, Romain, Iwawaki, Takao, Koliwad, Suneil K.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 22.03.2016; Elsevier
• Subjects: Animals; Bone Marrow Cells - cytology; Cells, Cultured; Diet; Endoplasmic Reticulum Stress - drug effects; Endoribonucleases - metabolism; Fatty Acids - pharmacology; Humans; Inflammasomes - metabolism; Interleukin-1beta - metabolism; Interleukin-1beta - secretion; Life Sciences; Lipopolysaccharides - toxicity; Macrophages - cytology; Macrophages - drug effects; Macrophages - metabolism; Male; Mice; Mice, Inbred C57BL; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Phosphatidylcholines - metabolism; Principal Component Analysis; Protein-Serine-Threonine Kinases - metabolism; Real-Time Polymerase Chain Reaction; Signal Transduction - drug effects; X-Box Binding Protein 1 - genetics; X-Box Binding Protein 1 - metabolism; unfolded protein response; obesity endoplasmic-reticulum; lipid-metabolism; innate immunity; er stress; a-diacylglycerol acyltransferase-1; thioredoxin-interacting protein; adipose-tissue macrophages; induced insulin-resistance; diet-induced
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2016.02.053

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. [Display omitted] •Saturated fatty acids induce an ER stress transcriptional signature in macrophages•Flux of saturated fatty acids into phospholipids activates the ER stress sensor IRE1α•IRE1α mediates saturated fatty-acid-induced activation of the NLRP3 inflammasome Excessive saturated fat consumption promotes tissue inflammation driven by “metabolically activated” macrophages. Here, Robblee et al. use transcriptomic profiling to identify the ER stress sensor IRE1α as a key component of metabolic activation that senses phospholipid saturation to mediate inflammatory activation in macrophages exposed to saturated fat.