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Inflammation and Atherosclerosis
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Inflammation and Atherosclerosis

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Immunology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 62029

Special Issue Editor

Prof. Dr. Klaus Ley

E-Mail Website
Guest Editor
1. Laboratory of Inflammation Biology, La Jolla Institute for Immunology, 9420 Athena Circle Drive, La Jolla, CA 92037, USA
2. Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA
Interests: My research is focused on the immunology of atherosclerosis. Most of our work concerns T cells that specifically recognize atherosclerosis epitopes, found for example in ApoB. We know that such epitopes exist in people, and the responses of these cells are different in cases (with atherosclerosis) and controls. We hope this can be exploited to build a vaccine to prevent atherosclerosis
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Atherosclerosis is a chronic disease of large arteries. Although age and low density lipoprotein cholesterol (LDL-C) are the most important risk factors, they do not fully explain the atherosclerosis risk or the incidence of major adverse cardiovascular events (MACE). In fact, even after accounting for all Framingham risk factors, at least 50% of the risk remains unexplained. Much of this residual risk is thought to be inflammatory. The recent CANTOS trial has shown that blocking the inflammatory cytokine IL-1β with the monoclonal antibody canakinumab reduces MACE incidence in patients with high levels of the inflammatory biomarker C-reactive protein (CRP). The inflammation component of atherosclerosis involves both the innate and the adaptive immune system. Many inflammation and immune molecules are significantly associated with MACE in genome-wide association studies (GWAS). This special issue encompasses contributions from leading researchers in the areas of inflammatory molecules, immune cells, and genetic risk scores.

Prof. Dr. Klaus Ley
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • Atherosclerosis
  • Inflammation
  • Immunity
  • IL-1β
  • Regulatory T cells
  • CD4 T cells
  • CD8 T cells
  • B cells
  • NK cells
  • ILCc
  • Monocytes
  • neutrophils

Published Papers (12 papers)

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Editorial

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3 pages, 173 KiB  
Editorial
Inflammation and Atherosclerosis
by Klaus Ley
Cells 2021, 10(5), 1197; https://doi.org/10.3390/cells10051197 - 14 May 2021
Cited by 13 | Viewed by 2425
Abstract
This 11-chapter Special Issue of Cells spans the gamut from basic science in mechanistic animal models to translational science to outcomes of clinical trials, all focused on the role of inflammation in atherosclerosis [...] Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)

Review

Jump to: Editorial

21 pages, 2389 KiB  
Review
Targeting Inflammatory Pathways in Cardiovascular Disease: The Inflammasome, Interleukin-1, Interleukin-6 and Beyond
by Peter Libby
Cells 2021, 10(4), 951; https://doi.org/10.3390/cells10040951 - 20 Apr 2021
Cited by 61 | Viewed by 6382
Abstract
Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number [...] Read more.
Recent clinical trials have now firmly established that inflammation participates causally in human atherosclerosis. These observations point the way toward novel treatments that add to established therapies to help stem the growing global epidemic of cardiovascular disease. Fortunately, we now have a number of actionable targets whose clinical exploration will help achieve the goal of optimizing beneficial effects while avoiding undue interference with host defenses or other unwanted actions. This review aims to furnish the foundation for this quest by critical evaluation of the current state of anti-inflammatory interventions within close reach of clinical application, with a primary focus on innate immunity. In particular, this paper highlights the pathway from the inflammasome, through interleukin (IL)-1 to IL-6 supported by a promising body of pre-clinical, clinical, and human genetic data. This paper also considers the use of biomarkers to guide allocation of anti-inflammatory therapies as a step toward realizing the promise of precision medicine. The validation of decades of experimental work and association studies in humans by recent clinical investigations provides a strong impetus for further efforts to target inflammation in atherosclerosis to address the considerable risk that remains despite current therapies. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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17 pages, 826 KiB  
Review
Regulatory T Cell-Enhancing Therapies to Treat Atherosclerosis
by Hafid Ait-Oufella, Jean-Rémi Lavillegrand and Alain Tedgui
Cells 2021, 10(4), 723; https://doi.org/10.3390/cells10040723 - 24 Mar 2021
Cited by 12 | Viewed by 3834
Abstract
Experimental studies have provided strong evidence that chronic inflammation triggered by the sub-endothelial accumulation of cholesterol-rich lipoproteins in arteries is essential in the initiation and progression of atherosclerosis. Recent clinical trials highlighting the efficacy of anti-inflammatory therapies in coronary patients have confirmed that [...] Read more.
Experimental studies have provided strong evidence that chronic inflammation triggered by the sub-endothelial accumulation of cholesterol-rich lipoproteins in arteries is essential in the initiation and progression of atherosclerosis. Recent clinical trials highlighting the efficacy of anti-inflammatory therapies in coronary patients have confirmed that this is also true in humans Monocytes/macrophages are central cells in the atherosclerotic process, but adaptive immunity, through B and T lymphocytes, as well as dendritic cells, also modulates the progression of the disease. Analysis of the role of different T cell subpopulations in murine models of atherosclerosis identified effector Th1 cells as proatherogenic, whereas regulatory T cells (Tregs) have been shown to protect against atherosclerosis. For these reasons, better understanding of how Tregs influence the atherosclerotic process is believed to provide novel Treg-targeted therapies to combat atherosclerosis. This review article summarizes current knowledge about the role of Tregs in atherosclerosis and discusses ways to enhance their function as novel immunomodulatory therapeutic approaches against cardiovascular disease. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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25 pages, 2866 KiB  
Review
ApoB-Specific CD4+ T Cells in Mouse and Human Atherosclerosis
by Timoteo Marchini, Sophie Hansen and Dennis Wolf
Cells 2021, 10(2), 446; https://doi.org/10.3390/cells10020446 - 19 Feb 2021
Cited by 17 | Viewed by 4393
Abstract
Atherosclerosis is a chronic inflammatory condition of the arterial wall that leads to the formation of vessel-occluding plaques within the subintimal space of middle-sized and larger arteries. While traditionally understood as a myeloid-driven lipid-storage disease, growing evidence suggests that the accumulation of low-density [...] Read more.
Atherosclerosis is a chronic inflammatory condition of the arterial wall that leads to the formation of vessel-occluding plaques within the subintimal space of middle-sized and larger arteries. While traditionally understood as a myeloid-driven lipid-storage disease, growing evidence suggests that the accumulation of low-density lipoprotein cholesterol (LDL-C) ignites an autoimmune response with CD4+ T-helper (TH) cells that recognize self-peptides from Apolipoprotein B (ApoB), the core protein of LDL-C. These autoreactive CD4+ T cells home to the atherosclerotic plaque, clonally expand, instruct other cells in the plaque, and induce clinical plaque instability. Recent developments in detecting antigen-specific cells at the single cell level have demonstrated that ApoB-reactive CD4+ T cells exist in humans and mice. Their phenotypes and functions deviate from classical immunological concepts of distinct and terminally differentiated TH immunity. Instead, ApoB-specific CD4+ T cells have a highly plastic phenotype, can acquire several, partially opposing and mixed transcriptional programs simultaneously, and transit from one TH subset into another over time. In this review, we highlight adaptive immune mechanisms in atherosclerosis with a focus on CD4+ T cells, introduce novel technologies to detect ApoB-specific CD4+ T cells at the single cell level, and discuss the potential impact of ApoB-driven autoimmunity in atherosclerosis. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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15 pages, 822 KiB  
Review
Inflammation-Related Risk Loci in Genome-Wide Association Studies of Coronary Artery Disease
by Carina Mauersberger, Heribert Schunkert and Hendrik B. Sager
Cells 2021, 10(2), 440; https://doi.org/10.3390/cells10020440 - 19 Feb 2021
Cited by 14 | Viewed by 2948
Abstract
Although the importance of inflammation in atherosclerosis is now well established, the exact molecular processes linking inflammation to the development and course of the disease are not sufficiently understood. In this context, modern genetics—as applied by genome-wide association studies (GWAS)—can serve as a [...] Read more.
Although the importance of inflammation in atherosclerosis is now well established, the exact molecular processes linking inflammation to the development and course of the disease are not sufficiently understood. In this context, modern genetics—as applied by genome-wide association studies (GWAS)—can serve as a comprehensive and unbiased tool for the screening of potentially involved pathways. Indeed, a considerable proportion of loci discovered by GWAS is assumed to affect inflammatory processes. Despite many well-replicated association findings, however, translating genomic hits to specific molecular mechanisms remains challenging. This review provides an overview of the currently most relevant inflammation-related GWAS findings in coronary artery disease and explores their potential clinical perspectives. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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29 pages, 4515 KiB  
Review
Act Locally, Act Globally—Microbiota, Barriers, and Cytokines in Atherosclerosis
by Natalia Kurilenko, Aliia R. Fatkhullina, Aleksandra Mazitova and Ekaterina K. Koltsova
Cells 2021, 10(2), 348; https://doi.org/10.3390/cells10020348 - 07 Feb 2021
Cited by 12 | Viewed by 3233
Abstract
Atherosclerosis is a lipid-driven chronic inflammatory disease that is characterized by the formation and progressive growth of atherosclerotic plaques in the wall of arteries. Atherosclerosis is a major predisposing factor for stroke and heart attack. Various immune-mediated mechanisms are implicated in the disease [...] Read more.
Atherosclerosis is a lipid-driven chronic inflammatory disease that is characterized by the formation and progressive growth of atherosclerotic plaques in the wall of arteries. Atherosclerosis is a major predisposing factor for stroke and heart attack. Various immune-mediated mechanisms are implicated in the disease initiation and progression. Cytokines are key mediators of the crosstalk between innate and adaptive immune cells as well as non-hematopoietic cells in the aortic wall and are emerging players in the regulation of atherosclerosis. Progression of atherosclerosis is always associated with increased local and systemic levels of pro-inflammatory cytokines. The role of cytokines within atherosclerotic plaque has been extensively investigated; however, the cell-specific role of cytokine signaling, particularly the role of cytokines in the regulation of barrier tissues tightly associated with microbiota in the context of cardiovascular diseases has only recently come to light. Here, we summarize the knowledge about the function of cytokines at mucosal barriers and the interplay between cytokines, barriers, and microbiota and discuss their known and potential implications for atherosclerosis development. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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28 pages, 2177 KiB  
Review
Functional Role of B Cells in Atherosclerosis
by Shelby D. Ma, Marion Mussbacher and Elena V. Galkina
Cells 2021, 10(2), 270; https://doi.org/10.3390/cells10020270 - 29 Jan 2021
Cited by 29 | Viewed by 4092
Abstract
Atherosclerosis is a lipid-driven inflammatory disease of blood vessels, and both innate and adaptive immune responses are involved in its development. The impact of B cells on atherosclerosis has been demonstrated in numerous studies and B cells have been found in close proximity [...] Read more.
Atherosclerosis is a lipid-driven inflammatory disease of blood vessels, and both innate and adaptive immune responses are involved in its development. The impact of B cells on atherosclerosis has been demonstrated in numerous studies and B cells have been found in close proximity to atherosclerotic plaques in humans and mice. B cells exert both atheroprotective and pro-atherogenic functions, which have been associated with their B cell subset attribution. While B1 cells and marginal zone B cells are considered to protect against atherosclerosis, follicular B cells and innate response activator B cells have been shown to promote atherosclerosis. In this review, we shed light on the role of B cells from a different, functional perspective and focus on the three major B cell functions: antibody production, antigen presentation/T cell interaction, and the release of cytokines. All of these functions have the potential to affect atherosclerosis by multiple ways and are dependent on the cellular milieu and the activation status of the B cell. Moreover, we discuss B cell receptor signaling and the mechanism of B cell activation under atherosclerosis-prone conditions. By summarizing current knowledge of B cells in and beyond atherosclerosis, we are pointing out open questions and enabling new perspectives. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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26 pages, 1420 KiB  
Review
Inflammatory Chemokines in Atherosclerosis
by Selin Gencer, Bryce R. Evans, Emiel P.C. van der Vorst, Yvonne Döring and Christian Weber
Cells 2021, 10(2), 226; https://doi.org/10.3390/cells10020226 - 25 Jan 2021
Cited by 98 | Viewed by 8419
Abstract
Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, [...] Read more.
Atherosclerosis is a long-term, chronic inflammatory disease of the vessel wall leading to the formation of occlusive or rupture-prone lesions in large arteries. Complications of atherosclerosis can become severe and lead to cardiovascular diseases (CVD) with lethal consequences. During the last three decades, chemokines and their receptors earned great attention in the research of atherosclerosis as they play a key role in development and progression of atherosclerotic lesions. They orchestrate activation, recruitment, and infiltration of immune cells and subsequent phenotypic changes, e.g., increased uptake of oxidized low-density lipoprotein (oxLDL) by macrophages, promoting the development of foam cells, a key feature developing plaques. In addition, chemokines and their receptors maintain homing of adaptive immune cells but also drive pro-atherosclerotic leukocyte responses. Recently, specific targeting, e.g., by applying cell specific knock out models have shed new light on their functions in chronic vascular inflammation. This article reviews recent findings on the role of immunomodulatory chemokines in the development of atherosclerosis and their potential for targeting. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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16 pages, 1259 KiB  
Review
CD8+ T Cells in Atherosclerosis
by Sarah Schäfer and Alma Zernecke
Cells 2021, 10(1), 37; https://doi.org/10.3390/cells10010037 - 29 Dec 2020
Cited by 53 | Viewed by 9415
Abstract
Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell [...] Read more.
Atherosclerotic lesions are populated by cells of the innate and adaptive immune system, including CD8+ T cells. The CD8+ T cell infiltrate has recently been characterized in mouse and human atherosclerosis and revealed activated, cytotoxic, and possibly dysfunctional and exhausted cell phenotypes. In mouse models of atherosclerosis, antibody-mediated depletion of CD8+ T cells ameliorates atherosclerosis. CD8+ T cells control monopoiesis and macrophage accumulation in early atherosclerosis. In addition, CD8+ T cells exert cytotoxic functions in atherosclerotic plaques and contribute to macrophage cell death and necrotic core formation. CD8+ T cell activation may be antigen-specific, and epitopes of atherosclerosis-relevant antigens may be targets of CD8+ T cells and their cytotoxic activity. CD8+ T cell functions are tightly controlled by costimulatory and coinhibitory immune checkpoints. Subsets of regulatory CD25+CD8+ T cells with immunosuppressive functions can inhibit atherosclerosis. Importantly, local cytotoxic CD8+ T cell responses may trigger endothelial damage and plaque erosion in acute coronary syndromes. Understanding the complex role of CD8+ T cells in atherosclerosis may pave the way for defining novel treatment approaches in atherosclerosis. In this review article, we discuss these aspects, highlighting the emerging and critical role of CD8+ T cells in atherosclerosis. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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16 pages, 1073 KiB  
Review
Monocyte Recruitment, Specification, and Function in Atherosclerosis
by Ki-Wook Kim, Stoyan Ivanov and Jesse W. Williams
Cells 2021, 10(1), 15; https://doi.org/10.3390/cells10010015 - 24 Dec 2020
Cited by 49 | Viewed by 5591
Abstract
Atherosclerotic lesions progress through the continued recruitment of circulating blood monocytes that differentiate into macrophages within plaque. Lesion-associated macrophages are the primary immune cells present in plaque, where they take up cholesterol and store lipids in the form of small droplets resulting in [...] Read more.
Atherosclerotic lesions progress through the continued recruitment of circulating blood monocytes that differentiate into macrophages within plaque. Lesion-associated macrophages are the primary immune cells present in plaque, where they take up cholesterol and store lipids in the form of small droplets resulting in a unique morphology termed foam cell. Recent scientific advances have used single-cell gene expression profiling, live-cell imaging, and fate mapping approaches to describe macrophage and monocyte contributions to pro- or anti-inflammatory mechanisms, in addition to functions of motility and proliferation within lesions. Yet, many questions regarding tissue-specific regulation of monocyte-to-macrophage differentiation and the contribution of recruited monocytes at stages of atherosclerotic disease progression remain unknown. In this review, we highlight recent advances regarding the role of monocyte and macrophage dynamics in atherosclerotic disease and identify gaps in knowledge that we hope will allow for advancing therapeutic treatment or prevention strategies for cardiovascular disease. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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15 pages, 726 KiB  
Review
Regulatory T Cell Stability and Plasticity in Atherosclerosis
by Amal J. Ali, Jeffrey Makings and Klaus Ley
Cells 2020, 9(12), 2665; https://doi.org/10.3390/cells9122665 - 11 Dec 2020
Cited by 40 | Viewed by 5094
Abstract
Regulatory T cells (Tregs) express the lineage-defining transcription factor FoxP3 and play crucial roles in self-tolerance and immune homeostasis. Thymic tTregs are selected based on affinity for self-antigens and are stable under most conditions. Peripheral pTregs differentiate from conventional CD4 T cells under [...] Read more.
Regulatory T cells (Tregs) express the lineage-defining transcription factor FoxP3 and play crucial roles in self-tolerance and immune homeostasis. Thymic tTregs are selected based on affinity for self-antigens and are stable under most conditions. Peripheral pTregs differentiate from conventional CD4 T cells under the influence of TGF-β and other cytokines and are less stable. Treg plasticity refers to their ability to inducibly express molecules characteristic of helper CD4 T cell lineages like T-helper (Th)1, Th2, Th17 or follicular helper T cells. Plastic Tregs retain FoxP3 and are thought to be specialized regulators for “their” lineage. Unstable Tregs lose FoxP3 and switch to become exTregs, which acquire pro-inflammatory T-helper cell programs. Atherosclerosis with systemic hyperlipidemia, hypercholesterolemia, inflammatory cytokines, and local hypoxia provides an environment that is likely conducive to Tregs switching to exTregs. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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26 pages, 1072 KiB  
Review
Vaccination in Atherosclerosis
by Felix Sebastian Nettersheim, Lauren De Vore and Holger Winkels
Cells 2020, 9(12), 2560; https://doi.org/10.3390/cells9122560 - 30 Nov 2020
Cited by 24 | Viewed by 4898
Abstract
Atherosclerosis is the major underlying pathology of cardiovascular diseases that together are the leading cause of death worldwide. The formation of atherosclerotic plaques is driven by chronic vascular inflammation. Although several risk factors have been identified and significant progress in disease prevention and [...] Read more.
Atherosclerosis is the major underlying pathology of cardiovascular diseases that together are the leading cause of death worldwide. The formation of atherosclerotic plaques is driven by chronic vascular inflammation. Although several risk factors have been identified and significant progress in disease prevention and treatment has been made, no therapeutic agents targeting inflammation are clinically available. Recent clinical trials established the potential of anti-inflammatory therapies as a treatment of atherosclerosis. However, adverse impacts on host defense have raised safety concerns about these therapies. Scientific evidence during the past 40 years implicated an adaptive immune response against plaque-associated autoantigens in atherogenesis. Preclinical data have underscored the protective potential of immunization against such targets precisely and without the impairment of host defense. In this review, we discuss the current vaccination strategies against atherosclerosis, supposed mechanisms of action, therapeutic potential, and the challenges that must be overcome in translating this idea into clinical practice. Full article
(This article belongs to the Special Issue Inflammation and Atherosclerosis)
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