Identifying a Role for the ER Stress Sensor IRE1α in Fatty Acid-Induced Inflammation

Diets rich in saturated fatty acids (SFAs) produce a form of tissue inflammation driven by “metabolically activated” macrophages, which contributes to the development of obesity-associated metabolic diseases. To better understand this form of macrophage activation, we analyzed the transcriptomes of mouse macrophages treated with either SFAs or the classical inflammatory stimulus lipopolysaccharide (LPS). SFA treatment induced a transcriptional signature distinct from that of LPS and strongly enriched by endoplasmic reticulum (ER) stress markers. In particular, SFA treatment increased the expression of the ER stress sensor IRE1α and many of its target genes comprising the adaptive unfolded protein response. SFAs also activate the NLRP3 inflammasome in macrophages, resulting in secretion of the pro-inflammatory cytokine IL-1β. 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. Instead, the ability of SFAs to stimulate either IRE1α activation or IL-1β secretion can be specifically reduced by preventing their flux into the phosphatidylcholine (PC) class of membrane lipids 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 and metabolic dysfunction