Targeting IRE1 with Small Molecules Counteracts Progression of Atherosclerosis
An important primer for inflammation in obesity is the chronic metabolic overloading of anabolic and catabolic organelles, such as the endoplasmic reticulum (ER) and mitochondria, leading to their functional impairment. The ER serves as a critical metabolic hub for protein, lipid, and calcium metabolism, and its vital functions are maintained by a conserved homeostatic stress response, known as the Unfolded Protein Response (UPR). Irremediable ER stress, however, can push the UPR towards pro-inflammatory and pro-apoptotic signaling. Activation of the UPR is a hallmark of all stages of atherosclerotic plaque formation, causally linking ER stress to atherosclerosis. There is profound interest in therapeutically limiting ER stress in many human diseases, which has driven the discovery of small molecules that can modulate specific aspects of UPR signaling. Small-molecule UPR modulators are excellent tools to understand the distinct contributions of the individual UPR signaling branches to atherogenesis. Inositol-requiring enzyme-1 (IRE1), a dual kinase and endoribonuclease (RNase), is one of three proximal UPR regulators. Using RNA sequencing, we discovered IRE1’s RNase activity regulates the expression of many pro-atherogenic genes, including cytokines, in macrophages. We show that inhibitors of IRE1’s RNase activity uncouple lipid-induced ER stress from inflammasome activation, and reduce inflammation in mouse and human macrophages. Furthermore, administrating two different inhibitors of IRE1’s RNase activity to hypercholestrolemic mice resulted in profound suppression of systemic and plaque-associated pro-atherogenic cytokine levels, T helper-1 type immune responses, and atherosclerosis. These results demonstrate that therapeutic modulation of IRE1 RNase activity with small-molecule inhibitors can alleviate atherosclerosis.
About The Speaker
Özlem Tufanlı has received her B.S. Degree in department of Biology at Middle East Technical University. She joined Bilkent University in 2011 to pursue her doctoral studies in department of Molecular Biology and Genetics under supervision of Dr. Ebru Erbay. Her main research interests lipotoxic endoplasmic reticulum stress in cardiometabolic syndrome: Novel mechanisms and therapeutic targets, which is supported through the Intensified Cooperation Grant between Turkey and Germany from the Scientific and Technological Research Council of Turkey (Collaborator Prof. Dr. Christian Weber, Ludwig Maximillians University). Her recent paper was published in PNAS in the title of “Targeting IRE1 with small molecules counteracts progression of atherosclerosis”.