Targeting IRE1 with small molecules counteracts progression of atherosclerosis


Tufanli O., Akillilar P. T., Acosta-Alvear D., KOCATÜRK B., Onat U. İ., Hamid S. M., ...More

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, vol.114, no.8, 2017 (SCI-Expanded) identifier identifier identifier identifier

  • Publication Type: Article / Article
  • Volume: 114 Issue: 8
  • Publication Date: 2017
  • Doi Number: 10.1073/pnas.1621188114
  • Journal Name: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
  • Journal Indexes: Science Citation Index Expanded (SCI-EXPANDED), Scopus
  • Keywords: endoplasmic reticulum stress, unfolded protein response, metaflammation, lipotoxicity, atherosclerosis, ENDOPLASMIC-RETICULUM-STRESS, UNFOLDED PROTEIN RESPONSE, MESSENGER-RNA, INFLAMMASOME ACTIVATION, SELECTIVE-INHIBITION, NLRP3 INFLAMMASOME, ER STRESS, IRE1-ALPHA, APOPTOSIS, PATHWAY
  • Acibadem Mehmet Ali Aydinlar University Affiliated: No

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-1 beta 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.