How the immune system shapes atherosclerosis: roles of innate and adaptive immunity

Roy, Payel; Orecchioni, Marco; Ley, Klaus

doi:10.1038/s41577-021-00584-1

Cited by 243 publications

(256 citation statements)

References 215 publications

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“…This allows for accumulation of lipids in the arterial intima, where they are oxidized, aggregate and are engulfed by smooth muscle cells (SMCs) and macrophages, causing foam cell formation (20)(21)(22)(23). Modified lipids act as chronic stimuli for innate and adaptive immune-responses that orchestrate a smoldering low-grade inflammation of the vessel wall (18). Subsequent cell apoptosis and necroptosis, complicated by failed efferocytosis (dead cell removal by phagocytes), cause formation of a lipid-rich necrotic core (NC) and production of thrombogenic tissue factor (21).…”

Section: Atherosclerotic Plaque Formation and Features Of Plaque Instabilitymentioning

confidence: 99%

“…Beyond the IL1-IL6-CRP axis and colchicine, a plethora of other promising targets within the innate and adaptive arm of the immune system are being explored ( 11 , 17 , 18 ). While these landmark trials have launched a thrilling new era of treatment in CVD, a more precise and conclusive understanding of the underlying immune mechanisms is essential to routinely apply and personalize the new therapeutic concepts.…”

Section: Clinical Relevancementioning

confidence: 99%

“…For an in depth discussion of the role of dendritic cells, mast cells, B cells, natural killer (NK) cells, and unconventional T-cells in atherosclerosis, we refer the reader to other recent and up-to-date review articles, respectively. Briefly, dendritic cells accumulate in plaques and form foam cells, regulate T-cell activation and proliferation by antigen-presentation, mediate efferocytosis and secrete immune-modulating cytokines and chemokines ( 18 , 57 , 58 ). Mast cells accumulate in the arterial adventitia and are activated to degranulate, releasing various mediators, some of which destabilize the plaque (proteases, proinflammatory cytokines), but also others that promote plaque stability by inhibiting thrombus formation or providing oxygen to hypoxic areas of the plaque ( 59 , 60 ).…”

Section: Immune Cells Crucially Drive Atherosclerosismentioning

confidence: 99%

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Immune Mechanisms of Plaque Instability

Gerhardt

Haghikia

Stapmanns

et al. 2022

Front. Cardiovasc. Med.

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Inflammation crucially drives atherosclerosis from disease initiation to the emergence of clinical complications. Targeting pivotal inflammatory pathways without compromising the host defense could compliment therapy with lipid-lowering agents, anti-hypertensive treatment, and lifestyle interventions to address the substantial residual cardiovascular risk that remains beyond classical risk factor control. Detailed understanding of the intricate immune mechanisms that propel plaque instability and disruption is indispensable for the development of novel therapeutic concepts. In this review, we provide an overview on the role of key immune cells in plaque inception and progression, and discuss recently identified maladaptive immune phenomena that contribute to plaque destabilization, including epigenetically programmed trained immunity in myeloid cells, pathogenic conversion of autoreactive regulatory T-cells and expansion of altered leukocytes due to clonal hematopoiesis. From a more global perspective, the article discusses how systemic crises such as acute mental stress or infection abruptly raise plaque vulnerability and summarizes recent advances in understanding the increased cardiovascular risk associated with COVID-19 disease. Stepping outside the box, we highlight the role of gut dysbiosis in atherosclerosis progression and plaque vulnerability. The emerging differential role of the immune system in plaque rupture and plaque erosion as well as the limitations of animal models in studying plaque disruption are reviewed.

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Section: Atherosclerotic Plaque Formation and Features Of Plaque Instabilitymentioning

confidence: 99%

Section: Clinical Relevancementioning

confidence: 99%

Section: Immune Cells Crucially Drive Atherosclerosismentioning

confidence: 99%

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Immune Mechanisms of Plaque Instability

Gerhardt

Haghikia

Stapmanns

et al. 2022

Front. Cardiovasc. Med.

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“…Atherosclerosis is a chronic condition of large- and medium-sized arteries that involves formation of leukocyte- and lipid-rich plaques in the arterial wall ( 1 ). Atherogenesis is accompanied and modulated by CD4 + T cells responding to plaque-associated autoantigens ( 2 , 3 ). One of these autoantigens is Apolipoprotein B (ApoB), the core protein of low-density lipoprotein (LDL) and other lipoprotein particles ( 2 ).…”

Section: Introductionmentioning

confidence: 99%

Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B

Nettersheim

Braumann²,

Kobiyama³

et al. 2022

Front. Cardiovasc. Med.

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Atherosclerosis is a chronic, lipid-driven disease of medium sized arteries which causes myocardial infarction and stroke. Recently, an adaptive immune response against the plaque-associated autoantigen Apolipoprotein B100 (ApoB), the structural protein component of low-density lipoprotein, has been implicated in atherogenesis. In healthy individuals, CD4+ T cells responding to ApoB mainly comprised regulatory T cells, which confer immune tolerance and atheroprotection. Mice and patients with atherosclerosis harbor increased numbers of proatherogenic ApoB-reactive T-helper cell subsets. Given the lack of therapies targeting proatherogenic immunity, clarification of the underlying mechanisms is of high clinical relevance. T cells develop in the thymus, where strong autoreactive T cells are eliminated in the process of negative selection. Herein, we investigated whether the transcription factor autoimmune regulator (AIRE), which controls expression of numerous tissue-restricted self-antigens in the thymus, is involved in mediating tolerance to ApoB and whether Aire deficiency might contribute to atherogenesis. Mice deficient for Aire were crossbred to apolipoprotein E-deficient mice to obtain atherosclerosis-prone Aire−/−Apoe−/− mice, which were fed a regular chow diet (CD) or western-type diet (WD). CD4+ T cells responding to the ApoB peptide p6 were analyzed by flow cytometry. We demonstrate that Aire deficiency influences neither generation nor activation of ApoB-reactive T cells and has only minor and overall inconsistent impacts on their phenotype. Furthermore, we show that atherosclerotic plaque size is not affected in Aire−/−Apoe−/− compared to Aire+/+Apoe−/−, irrespective of diet and gender. In conclusion, our data suggests that AIRE is not involved in regulating thymic expression of ApoB or atherosclerosis. Alternative mechanisms how ApoB-reactive CD4 T cells are selected in the thymus will have to be investigated.

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“…Following this step, the adaptive immune system can get activated and promote the plaque formation ( Miteva et al, 2018 ). Type 1 helper T (Th1) cells, type 2 helper T (Th2) cells, regulatory T (Treg) cells, CD4 + T cells and CD8 + T cells are the main contributors of the adaptive immune system involved in plaque formation and resolution ( Roy et al, 2021 ). The understanding of the mechanisms of immune responses involved in pathophysiology of inflammatory atherosclerosis not only bring in a realistic perception of the complexity of the disease but also inspire the development of novel therapeutics ( Ridker, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Nanotechnology for Targeted Therapy of Atherosclerosis

Nasr

Huang

2021

Front. Pharmacol.

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Atherosclerosis is the major cause of heart attack and stroke that are the leading causes of death in the world. Nanomedicine is a powerful tool that can be engineered to target atherosclerotic plaques for therapeutic and diagnosis purposes. In this review, advances in designing nanoparticles with therapeutic effects on atherosclerotic plaques known as atheroprotective nanomedicine have been summarized to stimulate further development and future translation.

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How the immune system shapes atherosclerosis: roles of innate and adaptive immunity

Cited by 243 publications

References 215 publications

Immune Mechanisms of Plaque Instability

Immune Mechanisms of Plaque Instability

Autoimmune Regulator (AIRE) Deficiency Does Not Affect Atherosclerosis and CD4 T Cell Immune Tolerance to Apolipoprotein B

Nanotechnology for Targeted Therapy of Atherosclerosis

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