Targeting IRE1 with small molecules counteracts progression of atherosclerosis
| Autor: | Umut Inci Onat, Pelin Telkoparan Akillilar, Christian Weber, Ozlem Tufanli, Syed M. Hamid, Diego Acosta-Alvear, Peter Walter, Ebru Erbay, Ismail Çimen, Begüm Kocatürk |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Male Chemokine Aging Unclassified drug Mouse Inflammasomes Interleukin-1beta Monocyte chemotactic protein 1 Apoptosis Endoplasmic Reticulum Inbred C57BL Cardiovascular Steady state Unfolded protein response Mice In vivo study Homeostasis 2.1 Biological and endogenous factors Bone marrow derived macrophage Aetiology Disease course Cells Cultured Protein inhibitor Priority journal Metaflammation Atherosclerotic plaque Multidisciplinary Cultured biology Kinase Th1 cell Messenger RNA Interleukin 1beta Interleukin-18 STF 083010 Hyperlipoproteinemia type 3 Inflammasome Atherogenesis Endoplasmic Reticulum Stress Gelatinase B Cell biology Hyperlipidemia Lipotoxicity PNAS Plus Disease Progression Endoplasmic reticulum stress Apolipoprotein E medicine.symptom Animal cell medicine.drug Signal Transduction Biotechnology Human Cells Inflammation RNA sequence Protein Serine-Threonine Kinases Article Mouse model Small Molecule Libraries 03 medical and health sciences Immune system Apolipoproteins E inflammasome medicine Animals Calgranulin A Animal model Animal experiment Immune response Endoplasmic reticulum Macrophages Membrane Proteins Gene targeting Interleukin 18 Atherosclerosis Nonhuman Lipid blood level Mice Inbred C57BL 030104 developmental biology Human cell Immunology Unfolded Protein Response biology.protein X box binding protein 1 Gene expression Protein IRE1 Reactive oxygen metabolite Controlled study |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America Proceedings of the National Academy of Sciences of the United States of America, vol 114, iss 8 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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