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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

Shami, Annelie LU orcid ; Atzler, Dorothee ; Bosmans, Laura A. ; Winkels, Holger ; Meiler, Svenja ; Lacy, Michael ; van Tiel, Claudia ; Ta Megens, Remco ; Nitz, Katrin and Baardman, Jeroen , et al. (2020) In European Heart Journal 41(31). p.2938-2948
Abstract

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.... (More)

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.

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publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atherosclerosis, Carotid artery, Co-stimulation, GITR, Monocyte
in
European Heart Journal
volume
41
issue
31
pages
11 pages
publisher
Oxford University Press
external identifiers
  • scopus:85090041415
  • pmid:32728688
ISSN
1522-9645
DOI
10.1093/eurheartj/ehaa484
language
English
LU publication?
yes
id
cbaac98a-46df-486a-be6c-169b83ea7c41
date added to LUP
2020-09-25 15:22:02
date last changed
2024-07-12 00:41:30
@article{cbaac98a-46df-486a-be6c-169b83ea7c41,
  abstract     = {{<p>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.</p>}},
  author       = {{Shami, Annelie and Atzler, Dorothee and Bosmans, Laura A. and Winkels, Holger and Meiler, Svenja and Lacy, Michael and van Tiel, Claudia and Ta Megens, Remco and Nitz, Katrin and Baardman, Jeroen and Kusters, Pascal and Seijkens, Tom and Buerger, Christina and Janjic, Aleksandar and Riccardi, Carlo and Edsfeldt, Andreas and Monaco, Claudia and Daemen, Mat and de Winther, Menno P.J. and Nilsson, Jan and Weber, Christian and Gerdes, Norbert and Gonçalves, Isabel and Lutgens, Esther}},
  issn         = {{1522-9645}},
  keywords     = {{Atherosclerosis; Carotid artery; Co-stimulation; GITR; Monocyte}},
  language     = {{eng}},
  number       = {{31}},
  pages        = {{2938--2948}},
  publisher    = {{Oxford University Press}},
  series       = {{European Heart Journal}},
  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}},
  url          = {{http://dx.doi.org/10.1093/eurheartj/ehaa484}},
  doi          = {{10.1093/eurheartj/ehaa484}},
  volume       = {{41}},
  year         = {{2020}},
}