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.
Atherosclerosis
Carotid artery
Co-stimulation
GITR
Monocyte
Journal
European heart journal
ISSN: 1522-9645
Titre abrégé: Eur Heart J
Pays: England
ID NLM: 8006263
Informations de publication
Date de publication:
14 08 2020
14 08 2020
Historique:
received:
11
12
2019
revised:
21
03
2020
accepted:
20
05
2020
pubmed:
31
7
2020
medline:
15
5
2021
entrez:
31
7
2020
Statut:
ppublish
Résumé
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). 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. 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.
Identifiants
pubmed: 32728688
pii: 5878259
doi: 10.1093/eurheartj/ehaa484
pmc: PMC9594689
doi:
Substances chimiques
Apolipoproteins E
0
Glucocorticoid-Induced TNFR-Related Protein
0
Glucocorticoids
0
Receptors, Tumor Necrosis Factor
0
TNFRSF18 protein, human
0
Tnfrsf18 protein, mouse
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2938-2948Commentaires et corrections
Type : CommentIn
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.
Références
Shock. 2011 Sep;36(3):263-71
pubmed: 21654556
J Am Coll Cardiol. 2018 Feb 6;71(5):527-542
pubmed: 29406859
Nat Immunol. 2014 May;15(5):473-81
pubmed: 24633226
Nat Biomed Eng. 2018 Aug;2(8):623
pubmed: 31015637
Cardiovasc Res. 2018 Mar 1;114(3):368-377
pubmed: 29309533
J Huazhong Univ Sci Technolog Med Sci. 2008 Oct;28(5):549-52
pubmed: 18846336
N Engl J Med. 2017 Sep 21;377(12):1119-1131
pubmed: 28845751
PLoS One. 2015 Oct 22;10(10):e0141019
pubmed: 26492161
Immunity. 2017 Oct 17;47(4):621-634
pubmed: 29045897
J Immunol Res. 2015;2015:762506
pubmed: 25759848
Immunology. 2006 Nov;119(3):421-9
pubmed: 17067317
Immunol Invest. 2008;37(4):359-73
pubmed: 18569075
J Immunol. 2006 Jul 1;177(1):631-41
pubmed: 16785561
PLoS One. 2007 Aug 22;2(8):e779
pubmed: 17712427
Circulation. 2008 Mar 11;117(10):1292-301
pubmed: 18285570
Acta Crystallogr D Biol Crystallogr. 2009 May;65(Pt 5):434-9
pubmed: 19390148
Arterioscler Thromb Vasc Biol. 2018 Aug;38(8):1678-1688
pubmed: 29930003
J Immunol. 2013 Nov 1;191(9):4573-80
pubmed: 24068673
J Autoimmun. 2006 Feb;26(1):24-31
pubmed: 16253477
Proc Natl Acad Sci U S A. 2000 Jun 20;97(13):7464-9
pubmed: 10861013
Br J Pharmacol. 2011 Mar;162(5):1186-201
pubmed: 21091650
Gastroenterology. 2012 Mar;142(3):582-591.e8
pubmed: 22155173
Br J Pharmacol. 2012 Apr;165(7):2089-99
pubmed: 22029729
J Clin Invest. 2007 Jan;117(1):195-205
pubmed: 17200719
Clin Exp Immunol. 2007 Jun;148(3):410-8
pubmed: 17359498
Proc Natl Acad Sci U S A. 2003 Dec 9;100(25):15059-64
pubmed: 14608036
Immunology. 2006 Dec;119(4):479-87
pubmed: 17177830
Nat Med. 2019 May;25(5):759-766
pubmed: 31036879
Endocrinology. 2006 Jan;147(1):70-8
pubmed: 16179414
Arterioscler Thromb Vasc Biol. 2000 May;20(5):1262-75
pubmed: 10807742
Proc Natl Acad Sci U S A. 1997 Jun 10;94(12):6216-21
pubmed: 9177197
Thromb Haemost. 2017 Jan 5;117(1):164-175
pubmed: 27786334
Clin Dev Immunol. 2013;2013:340751
pubmed: 23935647
Eur J Immunol. 2007 May;37(5):1165-9
pubmed: 17407102
J Immunol. 2009 Jun 15;182(12):7490-500
pubmed: 19494272
Circulation. 2012 Jan 17;125(2):364-74
pubmed: 22144566
Nat Immunol. 2002 Feb;3(2):135-42
pubmed: 11812990
Int J Rheum Dis. 2016 Feb;19(2):199-204
pubmed: 25293713
Atherosclerosis. 2001 Jul;157(1):75-84
pubmed: 11427206
J Exp Med. 2010 Feb 15;207(2):391-404
pubmed: 20100871
Eur Heart J. 2017 Dec 21;38(48):3590-3599
pubmed: 29045618
Arterioscler Thromb Vasc Biol. 2016 Sep;36(9):1748-52
pubmed: 27444204
J Clin Invest. 2007 Jan;117(1):185-94
pubmed: 17200718
Cell Immunol. 2008 May-Jun;253(1-2):92-101
pubmed: 18649874
Nat Med. 1999 Nov;5(11):1313-6
pubmed: 10546000
J Pharmacol Exp Ther. 2013 Oct;347(1):164-72
pubmed: 23892569
ScientificWorldJournal. 2007 May 01;7:533-66
pubmed: 17525820
Braz J Med Biol Res. 2014 Aug;47(8):662-9
pubmed: 25098715
Eur J Heart Fail. 2013 Sep;15(9):974-85
pubmed: 23603088
J Intern Med. 2015 Nov;278(5):462-82
pubmed: 25823439