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Updated: Mar 8, 2026
Quantitative Analysis of Cellular Composition in Advanced Atherosclerotic Lesions of Smooth Muscle Cell Lineage-Tracing Mice
Published on: February 20, 2019
Targeting IRE1 with small molecules counteracts progression of atherosclerosis
Ozlem Tufanli1,2, Pelin Telkoparan Akillilar1,2, Diego Acosta-Alvear3,4
1Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.
Abstract:
Metaflammation, an atypical, metabolically induced, chronic low-grade 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 ER-resident 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.
Insights
Metaflammation drives obesity and atherosclerosis by stressing endoplasmic reticulum (ER). Inhibiting the ER-resident kinase IRE1 reduces this stress, decreasing inflammatory markers and atherosclerotic plaque size.
Area of Science:
- Biomedical Science
- Immunology
- Cardiovascular Research
Background:
- Metaflammation, a chronic low-grade inflammation linked to metabolic diseases, arises from endoplasmic reticulum (ER) stress.
- The unfolded protein response (UPR), a cellular stress response, is activated during atherosclerosis.
- Inositol-requiring enzyme 1 (IRE1), a key UPR regulator, is present in macrophages within atherosclerotic lesions.
Purpose of the Study:
- To investigate the role of IRE1 in regulating proatherogenic gene expression in macrophages.
- To determine if IRE1 inhibition can mitigate metaflammation and atherosclerosis.
Main Methods:
- RNA sequencing was used to identify IRE1-regulated genes in macrophages.
- IRE1 inhibitors were tested in both mouse and human macrophages in vitro.
- Pharmacological inhibition of IRE1 was evaluated in apolipoprotein E-deficient mice with hyperlipidemia.
Main Results:
- IRE1 was found to regulate numerous proatherogenic genes, including cytokines and chemokines.
- IRE1 inhibitors effectively uncoupled ER stress from inflammasome activation in macrophages.
- In vivo, IRE1 inhibition reduced IL-1β and IL-18 production, suppressed T-helper type-1 responses, and decreased atherosclerotic plaque size.
Conclusions:
- Pharmacological targeting of IRE1 offers a potential therapeutic strategy to counteract metaflammation.
- Modulating IRE1 activity can alleviate atherosclerosis by reducing inflammation and plaque burden.
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