Browsing by Subject "Metaflammation"
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Item Open Access The role of IRE1 in metaflammation and atherosclerosis(2017-05) Tufanlı, ÖzlemChronic metabolic overloading of anabolic and catabolic organelles such as the endoplasmic reticulum (ER) and mitochondria is a major cause of inflammation in obesity. ER serves as a critical metabolic center for protein, lipid and calcium metabolism. ER’s vital functions are maintained by a conserved, adaptive stress response known as the Unfolded Protein Response (UPR), which strives to re-establish homeostasis. Irremediable ER stress, however, can push the UPR to initiate proinflammatory and pro-apoptotic signaling. UPR activation is seen in all stages of atherosclerotic plaque formation and ER stress is causally associated with atherosclerosis. A profound interest in therapeutically limiting ER stress in a variety of human diseases has driven the discovery of small molecules that can modulate specific UPR signaling arms. These UPR modulators can also become tools to understand the distinct contribution of UPR branches to atherogenesis. In my studies I utilized a specific inhibitor for Inositol-requiring enzyme-1 (IRE1), a dual kinase and endoribonuclease (RNase) in the UPR, to define IRE1’s RNA substrates in macrophages. Using RNA sequencing, I discovered that IRE1’s RNase activity regulates many pro-atherogenic and pro-inflammatory genes in macrophages. The outcome of my studies provides compelling evidence that IRE1, through its target XBP1, regulates the inflammatory response to lipid excess. The data shows that specific inhibitors of IRE1’s RNase activity can uncouple lipid-induced ER stress from immune response in both mouse and human macrophages by blocking mitochondrial reactive oxygen species production and NLRP3 inflammasome activation. Furthermore, administrating two small molecule inhibitors of IRE1’s RNase activity to hypercholestrolemic ApoE deficient (ApoE-/-) mice led to profound suppression of pro-atherogenic cytokine levels in the circulation and blunted T helper-1 type immune response, thus alleviating atherosclerosis. These results demonstrate that therapeutic fine-tuning of IRE1’s RNase activity with small molecule inhibitors could be developed further for atherosclerosis.Item Open Access Targeting IRE1 with small molecules counteracts progression of atherosclerosis(National Academy of Sciences, 2017-01) Tufanli, O.; Akillilar, P. T.; Acosta-Alvear, D.; Kocaturk, B.; Onat, U. I.; Hamid, S. M.; Çimen, I.; Walter, P.; Weber, C.; Erbay, E.Metaflammation, an atypical, metabolically induced, chronic lowgrade 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 ERresident 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.