The role of IRE1 in metaflammation and atherosclerosis
Author
Tufanlı, Özlem
Advisor
Erbay, Ebru
Date
2017-06Publisher
Bilkent University
Language
English
Type
ThesisItem Usage Stats
106
views
views
49
downloads
downloads
Abstract
Chronic 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.
Keywords
MetaflammationUnfolded protein response
Mitochondrial oxidative stress
Reactive oxygen species
Endoplasmic reticulum stress
Inflammasome
Atherosclerosis