Targeting IRE1 with small molecules counteracts progression of atherosclerosis
Akillilar, P. T.
Onat, U. I.
Hamid, S. M.
Proceedings of the National Academy of Sciences of the United States of America
National Academy of Sciences
E1395 - E1404
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Metaflammation, an atypical, metabolically induced, chronic lowgrade inflammation, plays an important role in the development of obesity, diabetes, and atherosclerosis. An important primer for metaflammation is the persistent metabolic overloading of the endoplasmic reticulum (ER), leading to its functional impairment. Activation of the unfolded protein response (UPR), a homeostatic regulatory network that responds to ER stress, is a hallmark of all stages of atherosclerotic plaque formation. The most conserved ERresident UPR regulator, the kinase/endoribonuclease inositol-requiring enzyme 1 (IRE1), is activated in lipid-laden macrophages that infiltrate the atherosclerotic lesions. Using RNA sequencing in macrophages, we discovered that IRE1 regulates the expression of many proatherogenic genes, including several important cytokines and chemokines. We show that IRE1 inhibitors uncouple lipid-induced ER stress from inflammasome activation in both mouse and human macrophages. In vivo, these IRE1 inhibitors led to a significant decrease in hyperlipidemia-induced IL-1β and IL-18 production, lowered T-helper type-1 immune responses, and reduced atherosclerotic plaque size without altering the plasma lipid profiles in apolipoprotein E-deficient mice. These results show that pharmacologic modulation of IRE1 counteracts metaflammation and alleviates atherosclerosis.
Endoplasmic reticulum stress
Unfolded protein response
Monocyte chemotactic protein 1
Reactive oxygen metabolite
X box binding protein 1
Bone marrow derived macrophage
Endoplasmic reticulum stress
Hyperlipoproteinemia type 3
In vivo study
Lipid blood level
Published Version (Please cite this version)https://doi.org/10.1073/pnas.1621188114
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