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
| العنوان: | 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 |
|---|---|
| المؤلفون: | Esther Lutgens, Norbert Gerdes, Claudia M. van Tiel, Dorothee Atzler, Claudia Monaco, Christian Weber, Pascal J. H. Kusters, Svenja Meiler, Tom Seijkens, Mat J.A.P. Daemen, Carlo Riccardi, Menno P.J. de Winther, Andreas Edsfeldt, Remco T. A. Megens, Isabel Gonçalves, Michael Lacy, Annelie Shami, Jan Nilsson, Katrin Nitz, Holger Winkels, Jeroen Baardman, C. Buerger, Aleksandar Janjic, Laura A Bosmans |
| المساهمون: | RS: Carim - B01 Blood proteins & engineering, Biochemie, Graduate School, ACS - Atherosclerosis & ischemic syndromes, AII - Inflammatory diseases, Medical Biochemistry, Pathology, Amsterdam Neuroscience - Neurovascular Disorders, ACS - Heart failure & arrhythmias |
| المصدر: | European Heart Journal, 41(31), 2938-2948. Oxford University Press European Heart Journal European heart journal, 41(31), 2938-2948. Oxford University Press |
| بيانات النشر: | Oxford University Press, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | STIMULATION, 030204 cardiovascular system & hematology, ligand, Monocyte, medicine.disease_cause, Receptors, Tumor Necrosis Factor, ACTIVATION, Mice, reduces atherosclerosis, 0302 clinical medicine, Medicine, Macrophage, MACROPHAGES, Mice, Knockout, 0303 health sciences, education.field_of_study, Fibrous cap, Interleukin, Plaque, Atherosclerotic, 3. Good health, Phenotype, medicine.anatomical_structure, MONOCYTES, medicine.symptom, Cardiology and Cardiovascular Medicine, EXPRESSION, Population, regulatory t-cells, EFFECTOR, Inflammation, PERIPHERAL-BLOOD, Co-stimulation, 03 medical and health sciences, Apolipoproteins E, Glucocorticoid-Induced TNFR-Related Protein, Animals, Humans, GITR, education, Glucocorticoids, 030304 developmental biology, carotid artery, business.industry, Atherosclerosis, Vulnerable plaque, Immune checkpoint, Mice, Inbred C57BL, Disease Models, Animal, Immunology, business |
| الوصف: | Aims GITR—a co-stimulatory immune checkpoint protein—is known for both its activating and regulating effects on T-cells. As atherosclerosis bears features of chronic inflammation and autoimmunity, we investigated the relevance of GITR in cardiovascular disease (CVD). Methods and results GITR expression was elevated in carotid endarterectomy specimens obtained from patients with cerebrovascular events (n = 100) compared to asymptomatic patients (n = 93) and correlated with parameters of plaque vulnerability, including plaque macrophage, lipid and glycophorin A content, and levels of interleukin (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−/−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. |
| اللغة: | English |
| تدمد: | 0195-668X |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::4a8737c2ccc2a8a318755cff77c500a5Test https://doi.org/10.1093/eurheartj/ehaa484Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....4a8737c2ccc2a8a318755cff77c500a5 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 0195668X |
|---|