Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier
Abstract Background Multiple sclerosis (MS) is an autoimmune disease which results from the invasion of the brain by activated immune cells across the endothelial cells (ECs) of the blood-brain barrier (BBB), due to loss of immune self-tolerance. Many reports define the metabolic profile of immune c...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-020-01810-8 |
| _version_ | 1818778611175391232 |
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| author | M. H. Sheikh S. M. Henson R. A. Loiola S. Mercurio A. Colamatteo G. T. Maniscalco V. De Rosa S. McArthur E. Solito |
| author_facet | M. H. Sheikh S. M. Henson R. A. Loiola S. Mercurio A. Colamatteo G. T. Maniscalco V. De Rosa S. McArthur E. Solito |
| author_sort | M. H. Sheikh |
| collection | DOAJ |
| description | Abstract Background Multiple sclerosis (MS) is an autoimmune disease which results from the invasion of the brain by activated immune cells across the endothelial cells (ECs) of the blood-brain barrier (BBB), due to loss of immune self-tolerance. Many reports define the metabolic profile of immune cells in MS, however little is known about the metabolism of the BBB ECs during the disease. We aim to determine whether circulating factors in MS induce metabolic alterations of the BBB ECs compared to a healthy state, which can be linked with disruption of BBB integrity and subsequent immune cell extravasation. Methods and results In this report, we used an in vitro model to study the effect of sera from naïve-to-treatment, relapsing-remitting MS (RRMS) patients on the human brain microvascular endothelium, comparing effects to age/sex-matched healthy donor (HD) sera. Our data show that RRMS serum components affect brain endothelial cells by impairing intercellular tightness through the down-modulation of occludin and VE-cadherin, and facilitating immune cell extravasation through upregulation of intercellular adhesion molecules (ICAM-1) and P-glycoprotein (P-gp). At a metabolic level, the treatment of the endothelial cells with RRMS sera reduced their glycolytic activity (measured through the extracellular acidification rate-ECAR) and oxygen consumption rate (oxidative phosphorylation rate-OCR). Such changes were associated with the down-modulation of endothelial glucose transporter 1 (GLUT-1) expression and by altered mitochondrial membrane potential. Higher level of reactive oxygen species released from the endothelial cells treated with RRMS sera indicate a pro-inflammatory status of the cells together with the higher expression of ICAM-1, endothelial cell cytoskeleton perturbation (stress fibres) as well as disruption of the cytoskeleton signal transduction MSK1/2 and β-catenin phosphorylation. Conclusions Our data suggest that circulating factors present in RRMS patient serum induce physiological and biochemical alterations to the BBB, namely reducing expression of essential tightness regulators, as well as reduced engagement of glycolysis and alteration of mitochondrial potential. As these last changes have been linked with alterations in nutrient usage and metabolic function in immune cells; we propose that the BBB endothelium of MS patients may similarly undergo metabolic dysregulation, leading to enhanced permeability and increased disease susceptibility. |
| first_indexed | 2024-12-18T11:47:28Z |
| format | Article |
| id | doaj.art-ec86bee898a346b4bcf7052818ebfa64 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-18T11:47:28Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-ec86bee898a346b4bcf7052818ebfa642022-12-21T21:09:15ZengBMCJournal of Neuroinflammation1742-20942020-05-0117111910.1186/s12974-020-01810-8Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrierM. H. Sheikh0S. M. Henson1R. A. Loiola2S. Mercurio3A. Colamatteo4G. T. Maniscalco5V. De Rosa6S. McArthur7E. Solito8John Vane Science Centre, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of LondonJohn Vane Science Centre, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of LondonJohn Vane Science Centre, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of LondonJohn Vane Science Centre, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of LondonDipartimento di Medicina Molecolare e Biotecnologie Mediche, Universitá degli Studi di Napoli “Federico II”Dipartimento di Neurologia, Centro Regionale Sclerosi Multipla, Azienda Ospedaliera “A. Cardarelli”Istituto per l’Endocrinologia e l’Oncologia Sperimentale “G. Salvatore”, IEOS-CNRInstitute of Dentistry, Barts and The London School of Medicine and Dentistry, Blizard Institute, Queen Mary University of LondonJohn Vane Science Centre, Barts and The London School of Medicine and Dentistry, William Harvey Research Institute, Queen Mary University of LondonAbstract Background Multiple sclerosis (MS) is an autoimmune disease which results from the invasion of the brain by activated immune cells across the endothelial cells (ECs) of the blood-brain barrier (BBB), due to loss of immune self-tolerance. Many reports define the metabolic profile of immune cells in MS, however little is known about the metabolism of the BBB ECs during the disease. We aim to determine whether circulating factors in MS induce metabolic alterations of the BBB ECs compared to a healthy state, which can be linked with disruption of BBB integrity and subsequent immune cell extravasation. Methods and results In this report, we used an in vitro model to study the effect of sera from naïve-to-treatment, relapsing-remitting MS (RRMS) patients on the human brain microvascular endothelium, comparing effects to age/sex-matched healthy donor (HD) sera. Our data show that RRMS serum components affect brain endothelial cells by impairing intercellular tightness through the down-modulation of occludin and VE-cadherin, and facilitating immune cell extravasation through upregulation of intercellular adhesion molecules (ICAM-1) and P-glycoprotein (P-gp). At a metabolic level, the treatment of the endothelial cells with RRMS sera reduced their glycolytic activity (measured through the extracellular acidification rate-ECAR) and oxygen consumption rate (oxidative phosphorylation rate-OCR). Such changes were associated with the down-modulation of endothelial glucose transporter 1 (GLUT-1) expression and by altered mitochondrial membrane potential. Higher level of reactive oxygen species released from the endothelial cells treated with RRMS sera indicate a pro-inflammatory status of the cells together with the higher expression of ICAM-1, endothelial cell cytoskeleton perturbation (stress fibres) as well as disruption of the cytoskeleton signal transduction MSK1/2 and β-catenin phosphorylation. Conclusions Our data suggest that circulating factors present in RRMS patient serum induce physiological and biochemical alterations to the BBB, namely reducing expression of essential tightness regulators, as well as reduced engagement of glycolysis and alteration of mitochondrial potential. As these last changes have been linked with alterations in nutrient usage and metabolic function in immune cells; we propose that the BBB endothelium of MS patients may similarly undergo metabolic dysregulation, leading to enhanced permeability and increased disease susceptibility.http://link.springer.com/article/10.1186/s12974-020-01810-8MetabolismMultiple sclerosisBlood-brain barrierTight junctionCytoskeleton |
| spellingShingle | M. H. Sheikh S. M. Henson R. A. Loiola S. Mercurio A. Colamatteo G. T. Maniscalco V. De Rosa S. McArthur E. Solito Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier Journal of Neuroinflammation Metabolism Multiple sclerosis Blood-brain barrier Tight junction Cytoskeleton |
| title | Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier |
| title_full | Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier |
| title_fullStr | Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier |
| title_full_unstemmed | Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier |
| title_short | Immuno-metabolic impact of the multiple sclerosis patients’ sera on endothelial cells of the blood-brain barrier |
| title_sort | immuno metabolic impact of the multiple sclerosis patients sera on endothelial cells of the blood brain barrier |
| topic | Metabolism Multiple sclerosis Blood-brain barrier Tight junction Cytoskeleton |
| url | http://link.springer.com/article/10.1186/s12974-020-01810-8 |
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