title: Targeting IRE1 with small molecules counteracts progression of atherosclerosis.
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.
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Ozlem
authors.initials: O
authors.lastname: Tufanli
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Pelin
authors.initials: P
authors.lastname: Telkoparan Akillilar
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, CA 94143.|Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
authors.forename: Diego
authors.initials: D
authors.lastname: Acosta-Alvear
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Begum
authors.initials: B
authors.lastname: Kocaturk
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Umut Inci
authors.initials: UI
authors.lastname: Onat
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Syed Muhammad
authors.initials: SM
authors.lastname: Hamid
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Ismail
authors.initials: I
authors.lastname: Çimen
authors.affiliation: Howard Hughes Medical Institute, University of California, San Francisco, CA 94143; peter@walterlab.ucsf.edu eerbay@bilkent.edu.tr.|Department of Biochemistry and Biophysics, University of California, San Francisco, CA 94143.
authors.forename: Peter
authors.identifier: 0000-0002-6849-708X
authors.initials: P
authors.lastname: Walter
authors.affiliation: Institute for Cardiovascular Prevention, Ludwig Maximilian University, Munich 80336, Germany.|German Centre for Cardiovascular Research, Munich Heart Alliance, Munich 80336, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Weber
authors.affiliation: Department of Molecular Biology and Genetics, Bilkent University, Ankara 06800, Turkey; peter@walterlab.ucsf.edu eerbay@bilkent.edu.tr.|National Nanotechnology Center, Bilkent University, Ankara 06800, Turkey.
authors.forename: Ebru
authors.identifier: 0000-0001-9584-1803
authors.initials: E
authors.lastname: Erbay
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000378:metabolism; D050197:Atherosclerosis / Q000188:drug therapy* / Q000378:metabolism*; D002478:Cells, Cultured; D018450:Disease Progression; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D006706:Homeostasis / Q000187:drug effects; D058847:Inflammasomes / Q000378:metabolism; D020382:Interleukin-18 / Q000378:metabolism; D053583:Interleukin-1beta / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000494:pharmacology*; D056811:Unfolded Protein Response / Q000187:drug effects
chemical_list: D001057:Apolipoproteins E; D058847:Inflammasomes; D020382:Interleukin-18; D053583:Interleukin-1beta; D008565:Membrane Proteins; D054852:Small Molecule Libraries; C486556:Ern2 protein, mouse; D017346:Protein Serine-Threonine Kinases
keywords: atherosclerosis; endoplasmic reticulum stress; lipotoxicity; metaflammation; unfolded protein response