Targeting IRE1 with small molecules counteracts progression of atherosclerosis.

摘要: Metaflammation, an atypical, metabolically induced, chronic low-grade inflammation, plays important role in the development of obesity, diabetes, and atherosclerosis. An primer for metaflammation is persistent metabolic overloading endoplasmic reticulum (ER), leading to its functional impairment. Activation unfolded protein response (UPR), a homeostatic regulatory network that responds ER stress, hallmark all stages atherosclerotic plaque formation. The most conserved ER-resident UPR regulator, kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), activated lipid-laden macrophages infiltrate lesions. Using RNA sequencing macrophages, we discovered IRE1 regulates expression many proatherogenic genes, including several cytokines chemokines. We show inhibitors uncouple lipid-induced stress from inflammasome activation both mouse human macrophages. In vivo, these led significant decrease hyperlipidemia-induced IL-1β IL-18 production, lowered T-helper type-1 immune responses, reduced size without altering plasma lipid profiles apolipoprotein E-deficient mice. These results pharmacologic modulation counteracts alleviates