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Wanted dead or alive: inflammatory macrophages in vascular disease
A Ted Rogers Centre for Heart Research and IBBME Special Seminar
Katey Rayner, PhD
Scientist & Director, Cardiometabolic microRNA Laboratory, University of Ottawa Heart Institute, and
Assistant Professor, Department of Biochemistry, Microbiology & Immunology, University of Ottawa
Atherosclerosis is considered a benign disease until plaques weaken and rupture, leading to acute thrombus and subsequent myocardial infarction or stroke. A hallmark of such vulnerable lesions is the presence of a large necrotic core covered by a thin fibrous cap, which renders the plaque susceptible to rupture.
While the processes that underlie the initiation of inflammatory fatty lesions within the arterial wall are well understood, the mechanisms by which these benign lesions develop into rupture-prone culprit lesions are not. There is thus an urgent need to better understand the pathways that contribute to necrotic core formation, and to develop strategies to target these processes therapeutically.
We recently described an important role for programmed necrosis, or necroptosis, in the development of vulnerable atherosclerosis in mice and humans. Necroptosis is an emerging cell death pathway involving RIP1, RIP3 and MLKL kinases.
The upstream stimuli of necroptosis are beginning to be defined, and we found that pro-atherogenic LDL (oxLDL) induces necroptotic cell death in a RIP3-dependent manner, and that treating mice with pre-existing atherosclerosis with a necroptosis inhibitor Nec-1 reduced plaque size and necrotic core formation.
Importantly, in humans with unstable carotid atherosclerosis, expression of RIP3 and MLKL is increased and MLKL phosphorylation, a key step in the commitment to necroptosis, is detected in advanced atheromas. We have also defined the importance of RIP1, an upstream kinase that regulates RIP3 and MLKL, in controlling cytokine production and inflammation in atherosclerosis.
In addition to cell death, the accumulation of lipid-laden macrophages in the artery wall results from the imbalance of monocyte recruitment to and macrophage emigration from plaque to regional lymph nodes. Thus, macrophage migration is central to the development of atherosclerosis.
We discovered that macrophages can promote pro-inflammatory and pro-atherogenic phenotypes in recipient cells through secretion of EVs containing miRNAs and can inhibit macrophage migration in vitro and in vivo. This effect appears to be mediated by the transfer of several miRNAs, including miR-146a, to recipient macrophages where they repress the expression of specific pro-migratory target genes.
Our studies suggest that EV-derived miRNAs secreted from atherogenic macrophages may accelerate the development of atherosclerosis lesions by decreasing cell migration and promoting macrophage entrapment in the vessel wall.
Together our work has uncovered novel pathways that underlie vascular disease development. We are now applying this knowledge to understand how inflammatory cells contribute to other immunometabolic diseases like diabetes and obesity.
In addition, we are developing novel diagnostic tools to identify plaques at their most critical state, as well as to better stratify patients for whom anti-inflammatory therapies may be of greatest benefit.
Katey Rayner is an assistant professor at the University of Ottawa Heart Institute in the Department of Biochemistry in Ottawa, Canada where she directs the Cardiometabolic microRNA Laboratory. Dr. Rayner obtained her BSc from the University of Toronto, and her PhD from the University of Ottawa.
Dr. Rayner’s doctoral work focused on the role of hormones, heat shock proteins and macrophage foam cells in the development of atherosclerosis. After her PhD, she pursued a postdoctoral fellowship first at Harvard Medical School/Massachusetts General Hospital then at New York University School of Medicine where Dr. Rayner helped to discover a role for microRNAs, specifically microRNA-33, in the regulation of HDL and its atheroprotective effects.
Since establishing her lab at the University of Ottawa, Dr. Rayner’s research program focuses on novel mechanisms that underlie the inflammatory processes of plaque progression and vulnerability, with a specific focus the intersection between macrophage inflammation and microRNAs as drivers of disease. Her group has uncovered a novel role for microRNA control of mitochondrial respiration in macrophage cholesterol efflux, which is aberrantly expressed in human atherosclerotic plaques.
Dr. Rayner’s research also examines how extracellular microRNAs are mediating the progression of atherosclerosis in both human and animal models. More recently, her group uncovered a role for programmed necrosis in the development of unstable plaques in mice and how this can get targeted as a therapeutic and diagnostic biomarker in humans.
Dr. Rayner serves on the editorial boards of Circulation Research and Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) where she also serves as the social media editor. She serves on peer review panels for granting agencies CIHR, NIH and Heart & Stroke Foundation and is the Chair of the Early Career Committee of the Council of ATVB at the American Heart Association.
Dr. Rayner has been recognized with awards such as the American Heart Association’s Irvine H Page Young Investigator Award, the Early Researcher Award from the Ministry of Innovation Ontario, and New Investigator Awards from both Canadian Institutes for Health Research and the Heart & Stroke Foundation.
Dr. Rayner’s research is currently funded by a Foundation Grant from the Canadian Institutes for Health Research, the Heart and Stroke Foundation of Canada and the National Institutes of Health.