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Blocking CCL5-CXCL4 heteromerization preserves heart function after myocardial infarction by attenuating leukocyte recruitment and NETosis

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      Abstract

      Myocardial infarction (MI) is a major cause of death in Western countries and finding new strategies for its prevention and treatment is thus of high priority. In a previous study, we have demonstrated a pathophysiologic relevance for the heterophilic interaction of CCL5 and CXCL4 in the progression of atherosclerosis. A specifically designed compound (MKEY) to block this CCL5-CXCR4 interaction is investigated as a potential therapeutic in a model of myocardial ischemia/reperfusion (I/R) damage. 8 week-old male C57BL/6 mice were intravenously treated with MKEY or scrambled control (sMKEY) from 1 day before, until up to 7 days after I/R. By using echocardiography and intraventricular pressure measurements, MKEY treatment resulted in a significant decrease in infarction size and preserved heart function as compared to sMKEY-treated animals. Moreover, MKEY treatment significantly reduced the inflammatory reaction following I/R, as revealed by specific staining for neutrophils and monocyte/macrophages. Interestingly, MKEY treatment led to a significant reduction of citrullinated histone 3 in the infarcted tissue, showing that MKEY can prevent neutrophil extracellular trap formation in vivo. Disrupting chemokine heterodimers during myocardial I/R might have clinical benefits, preserving the therapeutic benefit of blocking specific chemokines, and in addition, reducing the inflammatory side effects maintaining normal immune defence.

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      The healing myocardium sequentially mobilizes two monocyte subsets with divergent and complementary functions

      Healing of myocardial infarction (MI) requires monocytes/macrophages. These mononuclear phagocytes likely degrade released macromolecules and aid in scavenging of dead cardiomyocytes, while mediating aspects of granulation tissue formation and remodeling. The mechanisms that orchestrate such divergent functions remain unknown. In view of the heightened appreciation of the heterogeneity of circulating monocytes, we investigated whether distinct monocyte subsets contribute in specific ways to myocardial ischemic injury in mouse MI. We identify two distinct phases of monocyte participation after MI and propose a model that reconciles the divergent properties of these cells in healing. Infarcted hearts modulate their chemokine expression profile over time, and they sequentially and actively recruit Ly-6Chi and -6Clo monocytes via CCR2 and CX3CR1, respectively. Ly-6Chi monocytes dominate early (phase I) and exhibit phagocytic, proteolytic, and inflammatory functions. Ly-6Clo monocytes dominate later (phase II), have attenuated inflammatory properties, and express vascular–endothelial growth factor. Consequently, Ly-6Chi monocytes digest damaged tissue, whereas Ly-6Clo monocytes promote healing via myofibroblast accumulation, angiogenesis, and deposition of collagen. MI in atherosclerotic mice with chronic Ly-6Chi monocytosis results in impaired healing, underscoring the need for a balanced and coordinated response. These observations provide novel mechanistic insights into the cellular and molecular events that regulate the response to ischemic injury and identify new therapeutic targets that can influence healing and ventricular remodeling after MI.
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        Monocyte emigration from bone marrow during bacterial infection requires signals mediated by chemokine receptor CCR2.

        Monocytes recruited to tissues mediate defense against microbes or contribute to inflammatory diseases. Regulation of the number of circulating monocytes thus has implications for disease pathogenesis. However, the mechanisms controlling monocyte emigration from the bone marrow niche where they are generated remain undefined. We demonstrate here that the chemokine receptor CCR2 was required for emigration of Ly6C(hi) monocytes from bone marrow. Ccr2(-/-) mice had fewer circulating Ly6C(hi) monocytes and, after infection with Listeria monocytogenes, accumulated activated monocytes in bone marrow. In blood, Ccr2(-/-) monocytes could traffic to sites of infection, demonstrating that CCR2 is not required for migration from the circulation into tissues. Thus, CCR2-mediated signals in bone marrow determine the frequency of Ly6C(hi) monocytes in the circulation.
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          Monocyte subsets differentially employ CCR2, CCR5, and CX3CR1 to accumulate within atherosclerotic plaques.

          Monocytes participate critically in atherosclerosis. There are 2 major subsets expressing different chemokine receptor patterns: CCR2(+)CX3CR1(+)Ly-6C(hi) and CCR2(-)CX3CR1(++)Ly-6C(lo) monocytes. Both C-C motif chemokine receptor 2 (CCR2) and C-X(3)-C motif chemokine receptor 1 (CX3CR1) are linked to progression of atherosclerotic plaques. Here, we analyzed mouse monocyte subsets in apoE-deficient mice and traced their differentiation and chemokine receptor usage as they accumulated within atherosclerotic plaques. Blood monocyte counts were elevated in apoE(-/-) mice and skewed toward an increased frequency of CCR2(+)Ly-6C(hi) monocytes in apoE(-/-) mice fed a high-fat diet. CCR2(+)Ly-6C(hi) monocytes efficiently accumulated in plaques, whereas CCR2(-)Ly-6C(lo) monocytes entered less frequently but were more prone to developing into plaque cells expressing the dendritic cell-associated marker CD11c, indicating that phagocyte heterogeneity in plaques is linked to distinct types of entering monocytes. CCR2(-) monocytes did not rely on CX3CR1 to enter plaques. Instead, they were partially dependent upon CCR5, which they selectively upregulated in apoE(-/-) mice. By comparison, CCR2(+)Ly-6C(hi) monocytes unexpectedly required CX3CR1 in addition to CCR2 and CCR5 to accumulate within plaques. In many other inflammatory settings, these monocytes utilize CCR2, but not CX3CR1, for trafficking. Thus, antagonizing CX3CR1 may be effective therapeutically in ameliorating CCR2(+) monocyte recruitment to plaques without impairing their CCR2-dependent responses to inflammation overall.
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            Author and article information

            Affiliations
            [1 ]ISNI 0000 0001 0481 6099, GRID grid.5012.6, Cardiovascular Research Institute Maastricht (CARIM), Department of Biochemistry, , Maastricht University, ; Maastricht, The Netherlands
            [2 ]ISNI 0000 0004 1936 973X, GRID grid.5252.0, Institute for Cardiovascular Prevention (IPEK), , LMU Munich, ; Munich, Germany
            [3 ]ISNI 0000 0001 0728 696X, GRID grid.1957.a, Institute for Molecular Cardiovascular Research (IMCAR), , RWTH Aachen University, ; Aachen, Germany
            [4 ]ISNI 0000 0001 0728 696X, GRID grid.1957.a, Department of Experimental Molecular Imaging, , RWTH Aachen University, ; Aachen, Germany
            [5 ]ISNI 0000 0004 0369 4968, GRID grid.433858.1, Victor Babes National Institute of Pathology, ; Bucharest, Romania
            [6 ]GRID grid.5963.9, Department of Oral and Maxillofacial Surgery, , Karlsruhe City Hospital of Freiburg University, ; Freiburg, Germany
            [7 ]ISNI 0000 0001 2180 3484, GRID grid.13648.38, Department of Oral and Maxillofacial Surgery, , University Medical Center Hamburg-Eppendorf, ; Hamburg, Germany
            [8 ]DZHK (German Centre for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
            [9 ]ISNI 0000 0000 8653 1507, GRID grid.412301.5, Department of Cardiology, Pulmonology, Angiology and Intensive Care, , University Hospital Aachen, ; Aachen, Germany
            [10 ]ISNI 0000 0004 0384 6757, GRID grid.413055.6, Human Genetic Laboratory, , University of Medicine and Pharmacy, ; Craiova, Romania
            Contributors
            ORCID: http://orcid.org/0000-0002-9955-9730, r.koenen@maastrichtuniversity.nl
            Journal
            Sci Rep
            Sci Rep
            Scientific Reports
            Nature Publishing Group UK (London )
            2045-2322
            13 July 2018
            13 July 2018
            2018
            : 8
            30006564
            6045661
            29026
            10.1038/s41598-018-29026-0
            © 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: FundRef https://doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft (German Research Foundation);
            Award ID: SFB1123/A2
            Award ID: SFB1123/A2
            Award Recipient :
            Funded by: FundRef https://doi.org/10.13039/501100001826, ZonMw (Netherlands Organisation for Health Research and Development);
            Award ID: 016.126.358
            Award Recipient :
            Funded by: FundRef https://doi.org/10.13039/100009425, Landsteiner Foundation for Blood Transfusion Research (LSBR);
            Award ID: 1638
            Award Recipient :
            Funded by: FundRef https://doi.org/10.13039/501100000781, EC | European Research Council (ERC);
            Award ID: 249929
            Award Recipient :
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