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

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 IRE1 alpha and many adaptive downstream target genes. SFAs also activate the NLRP3 inflammasome in macrophages, resulting in IL-1 beta secretion. We found that IRE1 alpha mediates SFA-induced IL-1 beta 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 IRE1 alpha activation or IL-1 beta secretion can be specifically reduced by preventing their flux into phosphatidylcholine (PC) or by increasing unsaturated PC levels. Thus, IRE1 alpha is an unrecognized intracellular PC sensor critical to the process by which SFAs stimulate macrophages to secrete IL-1 beta, a driver of diet-induced tissue inflammation.