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Glucocorticoid induced TNF receptor family-related protein (GITR) – A novel driver of atherosclerosis

Bosmans, Laura A. ; Shami, Annelie LU orcid ; Atzler, Dorothee ; Weber, Christian ; Gonçalves, Isabel LU orcid and Lutgens, Esther (2021) In Vascular Pharmacology 139.
Abstract

Atherosclerosis is a lipid-driven, chronic inflammatory disease. In spite of efficient lipid lowering treatments, such as statins and PCSK9 inhibitors, patients, especially those with elevated inflammatory biomarkers, still have a significant residual cardiovascular disease risk. Novel drugs targeting inflammatory mediators are needed to further reduce this residual risk. Agonistic immune checkpoint proteins, including CD86, CD40L and CD40, have been shown to be drivers of atherosclerosis. Recently, glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR), a co-stimulatory immune checkpoint protein, was identified to be pivotal in cardiovascular disease. Cardiovascular patients have elevated soluble GITR... (More)

Atherosclerosis is a lipid-driven, chronic inflammatory disease. In spite of efficient lipid lowering treatments, such as statins and PCSK9 inhibitors, patients, especially those with elevated inflammatory biomarkers, still have a significant residual cardiovascular disease risk. Novel drugs targeting inflammatory mediators are needed to further reduce this residual risk. Agonistic immune checkpoint proteins, including CD86, CD40L and CD40, have been shown to be drivers of atherosclerosis. Recently, glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR), a co-stimulatory immune checkpoint protein, was identified to be pivotal in cardiovascular disease. Cardiovascular patients have elevated soluble GITR plasma levels compared to healthy controls. Furthermore, in human carotid endarterectomy plaques, GITR expression was higher in plaques from symptomatic compared to asymptomatic patients and correlated with features of plaque vulnerability. Moreover, depleting GITR reduced atherosclerotic plaque development in mice. GITR-deficient monocytes and macrophages exhibited less inflammatory potential and reduced migratory capacity. In this review, we discuss GITR's effects on various immune cells, mechanisms, signalling pathways and finally GITR's potential as a novel drug target in atherosclerosis.

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author
; ; ; ; and
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Atherosclerosis, Costimulatory molecule, CVD, GITR, Immune checkpoint
in
Vascular Pharmacology
volume
139
article number
106884
publisher
Elsevier
external identifiers
  • pmid:34102305
  • scopus:85107755710
ISSN
1537-1891
DOI
10.1016/j.vph.2021.106884
language
English
LU publication?
yes
id
6e8fb6a3-8722-4bbf-86e3-183ad91f7fcc
date added to LUP
2021-07-20 10:45:24
date last changed
2024-06-15 13:38:16
@article{6e8fb6a3-8722-4bbf-86e3-183ad91f7fcc,
  abstract     = {{<p>Atherosclerosis is a lipid-driven, chronic inflammatory disease. In spite of efficient lipid lowering treatments, such as statins and PCSK9 inhibitors, patients, especially those with elevated inflammatory biomarkers, still have a significant residual cardiovascular disease risk. Novel drugs targeting inflammatory mediators are needed to further reduce this residual risk. Agonistic immune checkpoint proteins, including CD86, CD40L and CD40, have been shown to be drivers of atherosclerosis. Recently, glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR), a co-stimulatory immune checkpoint protein, was identified to be pivotal in cardiovascular disease. Cardiovascular patients have elevated soluble GITR plasma levels compared to healthy controls. Furthermore, in human carotid endarterectomy plaques, GITR expression was higher in plaques from symptomatic compared to asymptomatic patients and correlated with features of plaque vulnerability. Moreover, depleting GITR reduced atherosclerotic plaque development in mice. GITR-deficient monocytes and macrophages exhibited less inflammatory potential and reduced migratory capacity. In this review, we discuss GITR's effects on various immune cells, mechanisms, signalling pathways and finally GITR's potential as a novel drug target in atherosclerosis.</p>}},
  author       = {{Bosmans, Laura A. and Shami, Annelie and Atzler, Dorothee and Weber, Christian and Gonçalves, Isabel and Lutgens, Esther}},
  issn         = {{1537-1891}},
  keywords     = {{Atherosclerosis; Costimulatory molecule; CVD; GITR; Immune checkpoint}},
  language     = {{eng}},
  publisher    = {{Elsevier}},
  series       = {{Vascular Pharmacology}},
  title        = {{Glucocorticoid induced TNF receptor family-related protein (GITR) – A novel driver of atherosclerosis}},
  url          = {{http://dx.doi.org/10.1016/j.vph.2021.106884}},
  doi          = {{10.1016/j.vph.2021.106884}},
  volume       = {{139}},
  year         = {{2021}},
}