Targeting IRE1 with small molecules counteracts progression of atherosclerosis.
Ozlem TufanliPelin Telkoparan AkillilarDiego Acosta-AlvearBegum KocaturkUmut Inci OnatSyed Muhammad HamidIsmail ÇimenPeter WalterChristian WeberEbru ErbayPublished in: Proceedings of the National Academy of Sciences of the United States of America (2017)
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.
Keyphrases
- endoplasmic reticulum stress
- endoplasmic reticulum
- low grade
- high glucose
- cardiovascular disease
- diabetic rats
- immune response
- endothelial cells
- type diabetes
- transcription factor
- drug induced
- coronary artery disease
- fatty acid
- high grade
- poor prognosis
- dendritic cells
- weight loss
- insulin resistance
- high fat diet
- gene expression
- quality improvement
- body mass index
- genome wide
- single cell
- dna methylation
- induced pluripotent stem cells
- skeletal muscle
- inflammatory response
- weight gain
- regulatory t cells
- adipose tissue
- network analysis
- small molecule
- emergency medicine