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Myeloid apolipoprotein E controls dendritic cell antigen presentation and T cell activation

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      Abstract

      Cholesterol homeostasis has a pivotal function in regulating immune cells. Here we show that apolipoprotein E (apoE) deficiency leads to the accumulation of cholesterol in the cell membrane of dendritic cells (DC), resulting in enhanced MHC-II-dependent antigen presentation and CD4 + T-cell activation. Results from WT and apoE KO bone marrow chimera suggest that apoE from cells of hematopoietic origin has immunomodulatory functions, regardless of the onset of hypercholesterolemia. Humans expressing apoE4 isoform (ε4/3–ε4/4) have increased circulating levels of activated T cells compared to those expressing WT apoE3 (ε3/3) or apoE2 isoform (ε2/3–ε2/2). This increase is caused by enhanced antigen-presentation by apoE4-expressing DCs, and is reversed when these DCs are incubated with serum containing WT apoE3. In summary, our study identifies myeloid-produced apoE as a key physiological modulator of DC antigen presentation function, paving the way for further explorations of apoE as a tool to improve the management of immune diseases.

      Abstract

      Cholesterol homeostasis can modulate immunity via multiple pathways. Here the authors show that apolipoprotein E, an important regulator of cholesterol, produced by myeloid cells can regulate T cell activation by controlling the antigen presentation activity of dendritic cells in both humans and mice.

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      Most cited references 76

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      Experimental work has elucidated molecular and cellular pathways of inflammation that promote atherosclerosis. Unraveling the roles of cytokines as inflammatory messengers provided a mechanism whereby risk factors for atherosclerosis can alter arterial biology, and produce a systemic milieu that favors atherothrombotic events. The discovery of the immune basis of allograft arteriosclerosis demonstrated that inflammation per se can drive arterial hyperplasia, even in the absence of traditional risk factors. Inflammation regulates aspects of plaque biology that trigger the thrombotic complications of atherosclerosis. Translation of these discoveries to humans has enabled both novel mechanistic insights and practical clinical advances.
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        The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor.

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          The immune response in atherosclerosis: a double-edged sword.

          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.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0004 1757 2822, GRID grid.4708.b, Department of Pharmacological and Biomolecular Sciences (DisFeB), , Università Degli Studi di Milano, ; Milan, 20133 Italy
            [2 ]ISNI 0000 0001 2171 1133, GRID grid.4868.2, William Harvey Research Institute, , Queen Mary University of London, ; London, EC1M 6BQ UK
            [3 ]ISNI 0000 0004 1759 8539, GRID grid.414266.3, SISA Centre, , Bassini Hospital, ; Cinisello Balsamo, 20092 Italy
            [4 ]ISNI 0000000417581884, GRID grid.18887.3e, San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), , IRCCS San Raffaele Scientific Institute, ; Milan, 20132 Italy
            [5 ]IRCSS Multimedica, Milan, 20138 Italy
            Contributors
            ORCID: http://orcid.org/0000-0002-6081-1257, danilo.norata@unimi.it
            Journal
            Nat Commun
            Nat Commun
            Nature Communications
            Nature Publishing Group UK (London )
            2041-1723
            6 August 2018
            6 August 2018
            2018
            : 9
            6079066 5322 10.1038/s41467-018-05322-1
            © The Author(s) 2018

            Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

            Funding
            Funded by: Ministero della Salute GR-2011-02346974
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