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      Macrophages and Their Role in Atherosclerosis: Pathophysiology and Transcriptome Analysis

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          Abstract

          Atherosclerosis can be regarded as a chronic inflammatory state, in which macrophages play different and important roles. Phagocytic proinflammatory cells populate growing atherosclerotic lesions, where they actively participate in cholesterol accumulation. Moreover, macrophages promote formation of complicated and unstable plaques by maintaining proinflammatory microenvironment. At the same time, anti-inflammatory macrophages contribute to tissue repair and remodelling and plaque stabilization. Macrophages therefore represent attractive targets for development of antiatherosclerotic therapy, which can aim to reduce monocyte recruitment to the lesion site, inhibit proinflammatory macrophages, or stimulate anti-inflammatory responses and cholesterol efflux. More studies are needed, however, to create a comprehensive classification of different macrophage phenotypes and to define their roles in the pathogenesis of atherosclerosis. In this review, we provide an overview of the current knowledge on macrophage diversity, activation, and plasticity in atherosclerosis and describe macrophage-based cellular tests for evaluation of potential antiatherosclerotic substances.

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          Most cited references68

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          Macrophage activation and polarization

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            Latent enhancers activated by stimulation in differentiated cells.

            According to current models, once the cell has reached terminal differentiation, the enhancer repertoire is completely established and maintained by cooperatively acting lineage-specific transcription factors (TFs). TFs activated by extracellular stimuli operate within this predetermined repertoire, landing close to where master regulators are constitutively bound. Here, we describe latent enhancers, defined as regions of the genome that in terminally differentiated cells are unbound by TFs and lack the histone marks characteristic of enhancers but acquire these features in response to stimulation. Macrophage stimulation caused sequential binding of stimulus-activated and lineage-determining TFs to these regions, enabling deposition of enhancer marks. Once unveiled, many of these enhancers did not return to a latent state when stimulation ceased; instead, they persisted and mediated a faster and stronger response upon restimulation. We suggest that stimulus-specific expansion of the cis-regulatory repertoire provides an epigenomic memory of the exposure to environmental agents. Copyright © 2013 Elsevier Inc. All rights reserved.
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              Cholesterol Crystals Activate the NLRP3 Inflammasome in Human Macrophages: A Novel Link between Cholesterol Metabolism and Inflammation

              Background Chronic inflammation of the arterial wall is a key element in the pathogenesis of atherosclerosis, yet the factors that trigger and sustain the inflammation remain elusive. Inflammasomes are cytoplasmic caspase-1-activating protein complexes that promote maturation and secretion of the proinflammatory cytokines interleukin(IL)-1β and IL-18. The most intensively studied inflammasome, NLRP3 inflammasome, is activated by diverse substances, including crystalline and particulate materials. As cholesterol crystals are abundant in atherosclerotic lesions, and IL-1β has been linked to atherogenesis, we explored the possibility that cholesterol crystals promote inflammation by activating the inflammasome pathway. Principal Findings Here we show that human macrophages avidly phagocytose cholesterol crystals and store the ingested cholesterol as cholesteryl esters. Importantly, cholesterol crystals induced dose-dependent secretion of mature IL-1β from human monocytes and macrophages. The cholesterol crystal-induced secretion of IL-1β was caspase-1-dependent, suggesting the involvement of an inflammasome-mediated pathway. Silencing of the NLRP3 receptor, the crucial component in NLRP3 inflammasome, completely abolished crystal-induced IL-1β secretion, thus identifying NLRP3 inflammasome as the cholesterol crystal-responsive element in macrophages. The crystals were shown to induce leakage of the lysosomal protease cathepsin B into the cytoplasm and inhibition of this enzyme reduced cholesterol crystal-induced IL-1β secretion, suggesting that NLRP3 inflammasome activation occurred via lysosomal destabilization. Conclusions The cholesterol crystal-induced inflammasome activation in macrophages may represent an important link between cholesterol metabolism and inflammation in atherosclerotic lesions.
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2016
                17 July 2016
                : 2016
                : 9582430
                Affiliations
                1Institute of General Pathology and Pathophysiology, Russian Academy of Medical Sciences, Moscow 125315, Russia
                2Faculty of Medicine, School of Medical Sciences, University of New South Wales, Kensington, Sydney, NSW 2052, Australia
                3School of Medicine, University of Western Sydney, Campbelltown, NSW 2560, Australia
                4Department of Development and Regeneration, KU Leuven, 3000 Leuven, Belgium
                5Department of Molecular Genetic Diagnostics and Cell Biology, Institute of Pediatrics, Research Center for Children's Health, Moscow 119991, Russia
                6Institute for Atherosclerosis, Skolkovo Innovation Center, Moscow 143025, Russia
                7Department of Biophysics, Biological Faculty, Moscow State University, Moscow 119991, Russia
                Author notes
                *Ekaterina A. Ivanova: kate.ivanov@ 123456gmail.com

                Academic Editor: Tomasz Guzik

                Author information
                http://orcid.org/0000-0002-3745-321X
                http://orcid.org/0000-0003-3159-2881
                http://orcid.org/0000-0002-6495-1628
                Article
                10.1155/2016/9582430
                4967433
                27493969
                32f6e92e-4042-4c4d-a233-dcb54243a156
                Copyright © 2016 Yuri V. Bobryshev et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 29 March 2016
                : 29 May 2016
                : 22 June 2016
                Funding
                Funded by: Russian Science Foundation
                Award ID: 14-15-00112
                Categories
                Review Article

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