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Cited by 16Atherosclerosis and Cardiovascular DiseasesCerebrovascular and Carotid Artery DiseasesCardiac Imaging and Diagnostics

Inflammation and features of the vulnerable plaque: from mechanisms and imaging to outcomes

Open access
Lüscher, Thomas F·2020·European Heart Journal
DOI 10.1093/eurheartj/ehaa686
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Abstract

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. The understanding of atherosclerosis has been markedly expanded in the last two decades with insights into inflammation as a major component of plaque development, erosion, and rupture. Although there is an overlap between cholesterol and inflammation, both are contributors to atherosclerosis in their own right.1 While atherosclerosis is a chronic inflammation induced by cholesterol, as the late Rudolf Virchow stated, inflammation alters endothelial function and contributes to the disease process also independently of lipids as documented by experimental2 and clinical studies.3–5 Inflammation importantly contributes to the vulnerability of plaques which are the substrate of acute coronary occlusion.6 A novel mechanism of plaque vulnerability, i.e. the glucocorticoid-induced tumour necrosis factor receptor family-related protein (GITR) an immune checkpoint protein regulating T cells, is presented in the article ‘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’ by Esther Lutgens and colleagues from the University of Amsterdam in the Netherlands.7 In patients with cerebrovascular events, GITR expression was elevated in carotid endarterectomy specimens compared with asymptomatic patients and correlated with parameters of plaque vulnerability such as an increased content of plaque macrophage, lipid, glycophorin A, interleukin-6 (IL-6) and IL-12, and C-C-chemokine ligand-2. Furthermore, soluble GITR levels were elevated in plasma from cardiovascular (CV) patients compared with healthy controls. The molecular mechanisms were assessed in Gitr–/–/Apoe–/– double knockout mice in which plaques were reduced and contained fewer macrophages, a smaller necrotic core, and thicker fibrous caps. RNA-sequencing of Gitr–/–/Apoe–/– and Apoe–/– monocytes and macrophages revealed altered pathways of cell migration, activation, and mitochondrial function, with decreased integrin levels, reduced recruitment to endothelium, and fewer reactive oxygen species. Likewise, GITR-deficient macrophages produced fewer cytokines and had a reduced migratory capacity. Thus, the immune checkpoint GITR drives myeloid cell recruitment and activation in atherosclerosis, thereby inducing plaque growth and vulnerability in mice and human plaques. GITR has the potential to become a novel therapeutic target in atherosclerosis (Figure 1), a conclusion that is further discussed in a educational Editorial by Michael Joner and colleagues from the Deutsches Herzzentrum Munchen in Germany.8 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 mice. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. (This figure was created in part using templates modified from Servier Medical Art (Mountain View, CA, USA, www.servier.com, licensed under a Creative Commons Attribution 3.0 Unported Licence) (from Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, Lutgens E. 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. See pages 2938–2948). 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 mice. In humans, elevated GITR expression in carotid plaques is associated with a vulnerable plaque phenotype and adverse cerebrovascular events. (This figure was created in part using templates modified from Servier Medical Art (Mountain View, CA, USA, www.servier.com, licensed under a Creative Commons Attribution 3.0 Unported Licence) (from Shami A, Atzler D, Bosmans LA, Winkels H, Meiler S, Lacy M, van Tiel C, Ta Megens R, Nitz K, Baardman J, Kusters P, Seijkens T, Buerger C, Janjic A, Riccardi C, Edsfeldt A, Monaco C, Daemen M, de Winther MPJ, Nilsson J, Weber C, Gerdes N, Gonçalves I, Lutgens E. 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. See pages 2938–2948). Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. Age-related dysbiosis enhances inflamm-ageing eventually accelerating atherogenesis. With ageing several endogenous and exogen

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  • Inflammation alters endothelial function and contributes to the vulnerability of plaques regardless of LDL-C levels.

    “Inflammation alters endothelial function and contributes to the vulnerability of plaques regardless of LDL-C levels (26).”

    From Triglycerides and residual atherosclerotic risk (2021) · cites this paper as [26]

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Authors
Lüscher, T. F.
Affiliations
University of Zurich (CH)
Corresponding author
Lüscher, Thomas F
ORCID
Lüscher, Thomas F
Venue
European Heart Journal
Publisher
Oxford University Press (OUP)
Published
2020-08-14
Volume
41
Issue
31
Pages
2923-2927
ISSN
  • 0195-668X (ISSN-L)
  • 1522-9645
DOI
10.1093/eurheartj/ehaa686
OpenAlex
W3082884533
Cited by
16
References
25
Citations by year
2026: 1 · 2025: 3 · 2024: 3 · 2023: 3 · 2022: 3 · 2021: 3
FWCI
0.79
Type
journal article
Language
en
Open access
Licence
Locations
  • European Heart Journal (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Atherosclerosis and Cardiovascular Diseases
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Cerebrovascular and Carotid Artery Diseases
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Cardiac Imaging and Diagnostics
Keywords
atherosclerosis, plaque vulnerability, inflammation, GITR, immune checkpoint, macrophage recruitment, myeloid cells, plaque rupture, acute coronary occlusion, cerebrovascular events, carotid endarterectomy, necrotic core, fibrous cap, cholesterol, endothelial function, therapeutic target, ApoE-deficient mice
MeSH terms
Diagnostic Imaging, Humans, Inflammation, Plaque, Atherosclerotic

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