According to the traditional view, atherosclerosis results from a passive buildup of cholesterol in the artery wall. Yet, burgeoning evidence implicates inflammation and immune effector mechanisms in ...the pathogenesis of this disease. Both innate and adaptive immunity operate during atherogenesis and link many traditional risk factors to altered arterial functions. Inflammatory pathways have become targets in the quest for novel preventive and therapeutic strategies against cardiovascular disease, a growing contributor to morbidity and mortality worldwide. Here we review current experimental and clinical knowledge of the pathogenesis of atherosclerosis through an immunological lens and how host defense mechanisms essential for survival of the species actually contribute to this chronic disease but also present new opportunities for its mitigation.
The view of atherosclerosis as an inflammatory disease has emerged from observations of immune activation and inflammatory signalling in human atherosclerotic lesions, from the definition of ...inflammatory biomarkers as independent risk factors for cardiovascular events, and from evidence of low-density lipoprotein-induced immune activation. Studies in animal models of hyperlipidaemia have also supported the beneficial effects of countering inflammation to delay atherosclerosis progression. Specific inflammatory pathways with relevance to human diseases have been identified, and inhibitors of these pathways are either already in use for the treatment of other diseases, or are under development and evaluation. These include 'classic' drugs (such as allopurinol, colchicine, and methotrexate), biologic therapies (for example tumour necrosis factor inhibitors and IL-1 neutralization), as well as targeting of lipid mediators (such as phospholipase inhibitors and antileukotrienes) or intracellular pathways (inhibition of NADPH oxidase, p38 mitogen-activated protein kinase, or phosphodiesterase). The evidence supporting the use of anti-inflammatory therapies for atherosclerosis is mainly based on either observational or small interventional studies evaluating surrogate markers of disease activity. Nevertheless, these data are crucial to understand the role of inflammation in atherosclerosis, and to design randomized controlled studies to evaluate the effect of specific anti-inflammatory strategies on cardiovascular outcomes.
Cardiovascular disease, a leading cause of mortality worldwide, is caused mainly by atherosclerosis, a chronic inflammatory disease of blood vessels. Lesions of atherosclerosis contain macrophages, T ...cells and other cells of the immune response, together with cholesterol that infiltrates from the blood. Targeted deletion of genes encoding costimulatory factors and proinflammatory cytokines results in less disease in mouse models, whereas interference with regulatory immunity accelerates it. Innate as well as adaptive immune responses have been identified in atherosclerosis, with components of cholesterol-carrying low-density lipoprotein triggering inflammation, T cell activation and antibody production during the course of disease. Studies are now under way to develop new therapies based on these concepts of the involvement of the immune system in atherosclerosis.
The immunology of atherosclerosis Gisterå, Anton; Hansson, Göran K
Nature reviews. Nephrology,
06/2017, Volume:
13, Issue:
6
Journal Article
Peer reviewed
Open access
Cardiovascular disease is the leading cause of death worldwide, both in the general population and among patients with chronic kidney disease (CKD). In most cases, the underlying cause of the ...cardiovascular event is atherosclerosis - a chronic inflammatory disease. CKD accelerates atherosclerosis via augmentation of inflammation, perturbation of lipid metabolism, and other mechanisms. In the artery wall, subendothelial retention of plasma lipoproteins triggers monocyte-derived macrophages and T helper type 1 (T
1) cells to form atherosclerotic plaques. Inflammation is initiated by innate immune reactions to modified lipoproteins and is perpetuated by T
1 cells that react to autoantigens from the apolipoprotein B100 protein of LDL. Other T cells are also active in atherosclerotic lesions; regulatory T cells inhibit pathological inflammation, whereas T
17 cells can promote plaque fibrosis. The slow build-up of atherosclerotic plaques is asymptomatic, but plaque rupture or endothelial erosion can induce thrombus formation, leading to myocardial infarction or ischaemic stroke. Targeting risk factors for atherosclerosis has reduced mortality, but a need exists for novel therapies to stabilize plaques and to treat arterial inflammation. Patients with CKD would likely benefit from such preventive measures.
Concepts of atherogenesis have evolved considerably with time. Early animal experiments showed that a cholesterol-rich diet could induce fatty lesion formation in arteries. The elucidation of ...lipoprotein metabolism ultimately led to demonstrating the clinical benefits of lipid lowering. The view of atheromata as bland accumulations of smooth muscle cells that elaborated an extracellular matrix that could entrap lipids then expanded to embrace inflammation as providing pathways that could link risk factors to atherogenesis. The characterization of leukocyte adhesion molecules and their control by proinflammatory cytokines, the ability of chemokines to recruit leukocytes, and the identification of inflammatory cell subtypes in lesions spurred the unraveling of innate and adaptive immune pathways that contribute to atherosclerosis and its thrombotic complications. Such pathophysiologic insights have led to the identification of biomarkers that can define categories of risk and direct therapies and to the development of new treatments.
Atherosclerosis is a chronic disease of the arterial wall, and a leading cause of death and loss of productive life years worldwide. Research into the disease has led to many compelling hypotheses ...about the pathophysiology of atherosclerotic lesion formation and of complications such as myocardial infarction and stroke. Yet, despite these advances, we still lack definitive evidence to show that processes such as lipoprotein oxidation, inflammation and immunity have a crucial involvement in human atherosclerosis. Experimental atherosclerosis in animals furnishes an important research tool, but extrapolation to humans requires care. Understanding how to combine experimental and clinical science will provide further insight into atherosclerosis and could lead to new clinical applications.
The hypothesis that immunity and inflammation participate in the pathogenesis of vascular diseases has now gained widespread recognition and stimulated work around the globe. Broadening knowledge has ...extended the recognition of the role of immune and inflammatory mechanisms to all of the layers of the artery, to all levels of the arterial tree, and implicated virtually all arms, cellular players, and effector molecules and pathways involved in these crucial host defenses, that turn against us in disease. We provide here a guide to a compendium series of articles that aimed to look forward and broaden the traditional focus of immunopathogenesis of arterial disease, with the goal of integrating the players and the layers involved. Although the field has advanced remarkably, much remains to be done, and this commentary also aims to highlight some of the gaps that future research should strive to close on the participation of inflammation and immunity in arterial diseases.
Adaptive as well as innate immune responses contribute to the development of atherosclerosis. Studies performed in experimental animals have revealed that some of these immune responses are ...protective while others contribute to the progression of disease. These observations suggest that it may be possible to develop novel therapies for cardiovascular disease by selectively modulating such atheroprotective and proatherogenic immunity. Recent advances in cancer treatment using immune check inhibitors and CAR (chimeric antigen receptor) T-cell therapy serve as excellent examples of the possibilities of targeting the immune system to combat disease. LDL (low-density lipoprotein) that has accumulated in the artery wall is a key autoantigen in atherosclerosis, and activation of antigen-specific T helper 1-type T cells is thought to fuel plaque inflammation. Studies aiming to prove this concept by immunizing experimental animals with oxidized LDL particles unexpectedly resulted in activation of atheroprotective immunity involving regulatory T cells. This prompted several research groups to try to develop vaccines against atherosclerosis. In this review, we will discuss the experimental and clinical data supporting the possibility of developing immune-based therapies for lowering cardiovascular risk. We will also summarize ongoing clinical studies and discuss the challenges associated with developing an effective and safe atherosclerosis vaccine.
Immune responses participate in every phase of atherosclerosis. There is increasing evidence that both adaptive and innate immunity tightly regulate atherogenesis. Although improved treatment of ...hyperlipidaemia reduces the risk for cardiac and cerebral complications of atherosclerosis, these remain among the most prevalent of diseases and will probably become the most common cause of death globally within 15 years. This Review focuses on the role of immune mechanisms in the formation and activation of atherosclerotic plaques, and also includes a discussion of the use of inflammatory markers for predicting cardiovascular events. We also outline possible future targets for prevention, diagnosis and treatment of atherosclerosis.
Until recently, most envisaged atherosclerosis as a bland arterial collection of cholesterol, complicated by smooth muscle cell accumulation. According to that concept, endothelial denuding injury ...led to platelet aggregation and release of platelet factors which would trigger the proliferation of smooth muscle cells in the arterial intima. These cells would then elaborate an extracellular matrix that would entrap lipoproteins, forming the nidus of the atherosclerotic plaque. Beyond the vascular smooth muscle cells long recognized in atherosclerotic lesions, subsequent investigations identified immune cells and mediators at work in atheromata, implicating inflammation in this disease. Multiple independent pathways of evidence now pinpoint inflammation as a key regulatory process that links multiple risk factors for atherosclerosis and its complications with altered arterial biology. Knowledge has burgeoned regarding the operation of both innate and adaptive arms of immunity in atherogenesis, their interplay, and the balance of stimulatory and inhibitory pathways that regulate their participation in atheroma formation and complication. This revolution in our thinking about the pathophysiology of atherosclerosis has now begun to provide clinical insight and practical tools that may aid patient management. This review provides an update of the role of inflammation in atherogenesis and highlights how translation of these advances in basic science promises to change clinical practice.
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