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      Downregulation of monocytic differentiation via modulation of CD147 by 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors

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          Abstract

          CD147 is an activation induced glycoprotein that promotes the secretion and activation of matrix metalloproteinases (MMPs) and is upregulated during the differentiation of macrophages. Interestingly, some of the molecular functions of CD147 rely on its glycosylation status: the highly glycosylated forms of CD147 induce MMPs whereas the lowly glycosylated forms inhibit MMP activation. Statins are hydroxy-methylglutaryl coenzyme A reductase inhibitors that block the synthesis of mevalonate, thereby inhibiting all mevalonate-dependent pathways, including isoprenylation, N-glycosylation and cholesterol synthesis. In this study, we investigated the role of statins in the inhibition of macrophage differentiation and the associated process of MMP secretion through modulation of CD147. We observed that differentiation of the human monocytic cell line THP-1 to a macrophage phenotype led to upregulation of CD147 and CD14 and that this effect was inhibited by statins. At the molecular level, statins altered CD147 expression, structure and function by inhibiting isoprenylation and N-glycosylation. In addition, statins induced a shift of CD147 from its highly glycosylated form to its lowly glycosylated form. This shift in N-glycosylation status was accompanied by a decrease in the production and functional activity of MMP-2 and MMP-9. In conclusion, these findings describe a novel molecular mechanism of immune regulation by statins, making them interesting candidates for autoimmune disease therapy.

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          Most cited references55

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          Macrophage phenotypes in atherosclerosis.

          Initiation and progression of atherosclerosis depend on local inflammation and accumulation of lipids in the vascular wall. Although many cells are involved in the development and progression of atherosclerosis, macrophages are fundamental contributors. For nearly a decade, the phenotypic heterogeneity and plasticity of macrophages has been studied. In atherosclerotic lesions, macrophages are submitted to a large variety of micro-environmental signals, such as oxidized lipids and cytokines, which influence the phenotypic polarization and activation of macrophages resulting in a dynamic plasticity. The macrophage phenotype spectrum is characterized, at the extremes, by the classical M1 macrophages induced by T-helper 1 (Th-1) cytokines and by the alternative M2 macrophages induced by Th-2 cytokines. M2 macrophages can be further classified into M2a, M2b, M2c, and M2d subtypes. More recently, additional plaque-specific macrophage phenotypes have been identified, termed as Mox, Mhem, and M4. Understanding the mechanisms and functional consequences of the phenotypic heterogeneity of macrophages will contribute to determine their potential role in lesion development and plaque stability. Furthermore, research on macrophage plasticity could lead to novel therapeutic approaches to counteract cardiovascular diseases such as atherosclerosis. The present review summarizes our current knowledge on macrophage subsets in atherosclerotic plaques and mechanism behind the modulation of the macrophage phenotype.
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            CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression.

            CD147 is a broadly expressed plasma membrane glycoprotein containing two immunoglobulin-like domains and a single charge-containing transmembrane domain. Here we use co-immunoprecipitation and chemical cross-linking to demonstrate that CD147 specifically interacts with MCT1 and MCT4, two members of the proton-linked monocarboxylate (lactate) transporter family that play a fundamental role in metabolism, but not with MCT2. Studies with a CD2-CD147 chimera implicate the transmembrane and cytoplasmic domains of CD147 in this interaction. In heart cells, CD147 and MCT1 co-localize, concentrating at the t-tubular and intercalated disk regions. In mammalian cell lines, expression is uniform but cross-linking with anti-CD147 antibodies caused MCT1, MCT4 and CD147, but not GLUT1 or MCT2, to redistribute together into 'caps'. In MCT-transfected cells, expressed protein accumulated in a perinuclear compartment, whereas co-transfection with CD147 enabled expression of active MCT1 or MCT4, but not MCT2, in the plasma membrane. We conclude that CD147 facilitates proper expression of MCT1 and MCT4 at the cell surface, where they remain tightly bound to each other. This association may also be important in determining their activity and location.
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              Pleiotropic effects of 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitors.

              The 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors or statins are potent inhibitors of cholesterol biosynthesis. Several large clinical trials have demonstrated the beneficial effects of statins in the primary and secondary prevention of coronary heart disease. However, the overall clinical benefits observed with statin therapy appear to be greater than what might be expected from changes in lipid profile alone, suggesting that the beneficial effects of statins may extend beyond their effects on serum cholesterol levels. Indeed, recent experimental and clinical evidence indicates that some of the cholesterol-independent or "pleiotropic" effects of statins involve improving or restoring endothelial function, enhancing the stability of atherosclerotic plaques, and decreasing oxidative stress and vascular inflammation. Many of these pleiotropic effects of statins are mediated by their ability to block the synthesis of important isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. In particular, the inhibition of small GTP-binding proteins, Rho, Ras, and Rac, whose proper membrane localization and function are dependent on isoprenylation, may play an important role in mediating the direct cellular effects of statins on the vascular wall.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing – original draftRole: Writing – review & editing
                Role: InvestigationRole: Writing – review & editing
                Role: SupervisionRole: Writing – review & editing
                Role: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                18 December 2017
                2017
                : 12
                : 12
                : e0189701
                Affiliations
                [1 ] Department of Neurology, Heinrich Heine University, Düsseldorf, Germany
                [2 ] Apollo Hospitals Educational and Research Foundation, Hyderabad, India
                [3 ] Department of Internal Medicine II, Molecular Biology and Medicine of the Lung, Justus Liebig University, Giessen, Germany
                [4 ] Wockhardt Research Centre, Aurangabad, India
                [5 ] Division of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, University of Colorado, Aurora, CO, United States of America
                [6 ] Department of Neurology, SRH Kliniken Landkreis Sigmaringen, Sigmaringen, Germany
                Klinikum rechts der Isar der Technischen Universitat Munchen, GERMANY
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0002-5496-2243
                Article
                PONE-D-17-31988
                10.1371/journal.pone.0189701
                5734787
                29253870
                86492133-aba4-499e-b263-6a8129cdb2af

                This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

                History
                : 31 August 2017
                : 30 November 2017
                Page count
                Figures: 8, Tables: 0, Pages: 19
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100001659, Deutsche Forschungsgemeinschaft;
                Award Recipient :
                Funded by: funder-id http://dx.doi.org/10.13039/100009091, Justus Liebig Universität Gießen;
                Award Recipient :
                This work was supported in part by grants from the Graduate College of the German Research Foundation, “Pathological processes of the nervous system: from gene to behaviour” (to MVS), and from the International Graduate Program of the Justus Liebig University of Giessen, “Molecular Biology and Medicine of the Lung” (to SKC).
                Categories
                Research Article
                Medicine and Health Sciences
                Pharmacology
                Drugs
                Statins
                Biology and Life Sciences
                Developmental Biology
                Cell Differentiation
                Biology and Life Sciences
                Biochemistry
                Lipids
                Cholesterol
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Macrophages
                Biology and Life Sciences
                Biochemistry
                Glycobiology
                Glycosylation
                Biology and Life Sciences
                Biochemistry
                Proteins
                Post-Translational Modification
                Glycosylation
                Medicine and Health Sciences
                Clinical Medicine
                Clinical Immunology
                Autoimmune Diseases
                Multiple Sclerosis
                Biology and Life Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Multiple Sclerosis
                Medicine and Health Sciences
                Immunology
                Clinical Immunology
                Autoimmune Diseases
                Multiple Sclerosis
                Medicine and Health Sciences
                Neurology
                Demyelinating Disorders
                Multiple Sclerosis
                Medicine and Health Sciences
                Neurology
                Neurodegenerative Diseases
                Multiple Sclerosis
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Blood Cells
                White Blood Cells
                Monocytes
                Biology and Life Sciences
                Cell Biology
                Cellular Types
                Animal Cells
                Immune Cells
                White Blood Cells
                Monocytes
                Biology and Life Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Monocytes
                Medicine and Health Sciences
                Immunology
                Immune Cells
                White Blood Cells
                Monocytes
                Research and Analysis Methods
                Spectrum Analysis Techniques
                Spectrophotometry
                Cytophotometry
                Flow Cytometry
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