@article{c0046d9278264640bbf98ee68a13fb0d,
title = "Glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) drives atherosclerosis in mice and is associated with an unstable plaque phenotype and cerebrovascular events in humans",
abstract = "Aims GITR a co-stimulatory immune checkpoint protein is known for both its activating and regulating effects on Tcells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD).Methods GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular and results events (n= 100) compared to asymptomatic patients (n= 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and gtycophorin A content, and levels of interteukin (IL) -6, IL-12, and C-C-chemokine ligand 2. Soluble GITR levels were elevated in plasma from subjects with CVD compared to healthy controls. Plaque area in 28-week-old Gitr(-/-) Apoe(-/-) mice was reduced, and plaques had a favourable phenotype with Less macrophages, a smaller necrotic core and a thicker fibrous cap. GITR deficiency did not affect the lymphoid population. RNA sequencing of Gitr(-/-) Apoe(-/-)and Apoe(-/-) monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function. Indeed, Gitr I Apoe monocytes displayed decreased integrin levels, reduced recruitment to endothelium, and produced less reactive oxygen species. Likewise, GITR-deficient macrophages produced less cytokines and had a reduced migratory capacity.Conclusion Our data reveal a novel role for the immune checkpoint GITR in driving myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. GITR has the potential to become a novel therapeutic target in atherosclerosis as it reduces myeloid cell recruitment to the arterial wall and impedes atherosclerosis progression.",
keywords = "activation, atherosclerosis, carotid artery, co-stimulation, effector, expression, gitr, ligand, macrophages, monocyte, monocytes, peripheral-blood, reduces atherosclerosis, regulatory t-cells, stimulation, GITR, ACTIVATION, Co-stimulation, PERIPHERAL-BLOOD, Atherosclerosis, REGULATORY T-CELLS, Carotid artery, LIGAND, STIMULATION, Monocyte, MACROPHAGES, MONOCYTES, EFFECTOR, REDUCES ATHEROSCLEROSIS, EXPRESSION",
author = "A. Shami and D. Atzler and L.A. Bosmans and H. Winkels and S. Meiler and M. Lacy and {van Tiel}, C. and R.T. Megens and K. Nitz and J. Baardman and P. Kusters and T. Seijkens and C. Buerger and A. Janjic and C. Riccardi and A. Edsfeldt and C. Monaco and M. Daemen and {de Winther}, M.P.J. and J. Nilsson and C. Weber and N. Gerdes and I. Goncalves and E. Lutgens",
note = "Funding Information: The authors would like to thank Linda Beckers, Myrthe den Toom, Kikkie Poels, Sigrid Reim, Yvonne Janssen, Mihaela Nitulescu, Lena Sundius, Ana Persson, Pratibha Singh for excellent technical support. Christian Weber is a Van de Laar professor of atherosclerosis. Flow cytometry experiments on human tissue were performed at the LUDC-Flow Cytometry Core Facility and was supported by the Swedish Research Council, Strategic Research Area Exodiab (Dnr 2009-1039), and by the Swedish Foundation for Strategic Research (Dnr IRC15-0067). The Swedish Heart and Lung Foundation (20150325, 20140206, 20180056 to A.S., 20170333, 20140327, 20140078 to I.G., 20170437 to A.E.); the Swedish Research Council (2015-00497 to A.S., 2015-02523 to I.G.); Sk?nes University Hospital (2019-o000032 to I.G.); Southern Sweden Regional Research Funding (REGSKANE-633571 to I.G.); Sparbanks F?rs and Frosta Foundation (V2016/405 to I.G.); Diabetes Foundation (DIA2017-242 to I.G.), and The Swedish Society for Medical Research (A.E). We also acknowledge the support from the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, Dutch Federation of University Medical Centres, the Netherlands Organization for Health Research, and Development and the Royal Netherlands Academy of Sciences for the GENIUS-II project 'Generating the best evidence-based pharmaceutical targets for atherosclerosis' (CVON2017-20 to E.L., M.d.W., J.B.), the Deutsche Forschungsgemeinschaft (CRC 1123 to D.A., E.L., N.G., R.M., C.W.); the Netherlands Organization for Scientific Research (NWO) (VICI grant to E.L.); the EU (Horizon 2020, REPROGRAM to E.L., M.d.W.,); the European Research Council (ERC consolidator grant to E.L, ERC advanced grant to C.W.); and the Fondation Leducq Transatlantic Network Grant (16CVD01 to M.d.W.). Publisher Copyright: {\textcopyright} The Author(s) 2020.",
year = "2020",
month = aug,
day = "14",
doi = "10.1093/eurheartj/ehaa484",
language = "English",
volume = "41",
pages = "2938--2948",
journal = "European Heart Journal",
issn = "0195-668X",
publisher = "Oxford University Press",
number = "31",
}