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

SUBMITTER: Robblee MM 

PROVIDER: S-EPMC5242525 | biostudies-literature | 2016 Mar

REPOSITORIES: biostudies-literature