Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation
Abstract Background The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeu...
| Main Authors: | , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2017-05-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-017-0875-9 |
| _version_ | 1819056028682027008 |
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| author | Suzanne A. B. M. Aarts Tom T. P. Seijkens Pascal J. H. Kusters Susanne M. A. van der Pol Barbara Zarzycka Priscilla D. A. M. Heijnen Linda Beckers Myrthe den Toom Marion J. J. Gijbels Louis Boon Christian Weber Helga E. de Vries Gerry A. F. Nicolaes Christine D. Dijkstra Gijs Kooij Esther Lutgens |
| author_facet | Suzanne A. B. M. Aarts Tom T. P. Seijkens Pascal J. H. Kusters Susanne M. A. van der Pol Barbara Zarzycka Priscilla D. A. M. Heijnen Linda Beckers Myrthe den Toom Marion J. J. Gijbels Louis Boon Christian Weber Helga E. de Vries Gerry A. F. Nicolaes Christine D. Dijkstra Gijs Kooij Esther Lutgens |
| author_sort | Suzanne A. B. M. Aarts |
| collection | DOAJ |
| description | Abstract Background The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation. Methods Human monocytes were treated with a small molecule inhibitor (SMI) of CD40-TRAF6 interactions (6877002), and migration capacity across human brain endothelial cells was measured. To test the therapeutic potential of the CD40-TRAF6-blocking SMI under neuro-inflammatory conditions in vivo, Lewis rats and C57BL/6J mice were subjected to acute experimental autoimmune encephalomyelitis (EAE) and treated with SMI 6877002 for 6 days (rats) or 3 weeks (mice). Results We here show that a SMI of CD40-TRAF6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. Moreover, upon SMI treatment, monocytes displayed a decreased production of ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS. |
| first_indexed | 2024-12-21T13:16:54Z |
| format | Article |
| id | doaj.art-3098d45e563e46008b1ee78f986c3e30 |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-21T13:16:54Z |
| publishDate | 2017-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-3098d45e563e46008b1ee78f986c3e302022-12-21T19:02:41ZengBMCJournal of Neuroinflammation1742-20942017-05-0114111410.1186/s12974-017-0875-9Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammationSuzanne A. B. M. Aarts0Tom T. P. Seijkens1Pascal J. H. Kusters2Susanne M. A. van der Pol3Barbara Zarzycka4Priscilla D. A. M. Heijnen5Linda Beckers6Myrthe den Toom7Marion J. J. Gijbels8Louis Boon9Christian Weber10Helga E. de Vries11Gerry A. F. Nicolaes12Christine D. Dijkstra13Gijs Kooij14Esther Lutgens15Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamDepartment of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamDepartment of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamDepartment of Molecular Cell Biology and Immunology, VU University Medical CenterDepartment of Biochemistry, University of MaastrichtDepartment of Molecular Cell Biology and Immunology, VU University Medical CenterDepartment of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamDepartment of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamDepartment of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamBiocerosInstitute for Cardiovascular Prevention (IPEK), Ludwig Maximilians University (LMU)Department of Molecular Cell Biology and Immunology, VU University Medical CenterDepartment of Biochemistry, University of MaastrichtDepartment of Molecular Cell Biology and Immunology, VU University Medical CenterDepartment of Molecular Cell Biology and Immunology, VU University Medical CenterDepartment of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of AmsterdamAbstract Background The influx of leukocytes into the central nervous system (CNS) is a key hallmark of the chronic neuro-inflammatory disease multiple sclerosis (MS). Strategies that aim to inhibit leukocyte migration across the blood-brain barrier (BBB) are therefore regarded as promising therapeutic approaches to combat MS. As the CD40L-CD40 dyad signals via TNF receptor-associated factor 6 (TRAF6) in myeloid cells to induce inflammation and leukocyte trafficking, we explored the hypothesis that specific inhibition of CD40-TRAF6 interactions can ameliorate neuro-inflammation. Methods Human monocytes were treated with a small molecule inhibitor (SMI) of CD40-TRAF6 interactions (6877002), and migration capacity across human brain endothelial cells was measured. To test the therapeutic potential of the CD40-TRAF6-blocking SMI under neuro-inflammatory conditions in vivo, Lewis rats and C57BL/6J mice were subjected to acute experimental autoimmune encephalomyelitis (EAE) and treated with SMI 6877002 for 6 days (rats) or 3 weeks (mice). Results We here show that a SMI of CD40-TRAF6 interactions (6877002) strongly and dose-dependently reduces trans-endothelial migration of human monocytes. Moreover, upon SMI treatment, monocytes displayed a decreased production of ROS, tumor necrosis factor (TNF), and interleukin (IL)-6, whereas the production of the anti-inflammatory cytokine IL-10 was increased. Disease severity of EAE was reduced upon SMI treatment in rats, but not in mice. However, a significant reduction in monocyte-derived macrophages, but not in T cells, that had infiltrated the CNS was eminent in both models. Conclusions Together, our results indicate that SMI-mediated inhibition of the CD40-TRAF6 pathway skews human monocytes towards anti-inflammatory cells with reduced trans-endothelial migration capacity, and is able to reduce CNS-infiltrated monocyte-derived macrophages during neuro-inflammation, but minimally ameliorates EAE disease severity. We therefore conclude that SMI-mediated inhibition of the CD40-TRAF6 pathway may represent a beneficial treatment strategy to reduce monocyte recruitment and macrophage activation in the CNS and has the potential to be used as a co-treatment to combat MS.http://link.springer.com/article/10.1186/s12974-017-0875-9Multiple sclerosisEAECo-stimulationMonocytesInflammation |
| spellingShingle | Suzanne A. B. M. Aarts Tom T. P. Seijkens Pascal J. H. Kusters Susanne M. A. van der Pol Barbara Zarzycka Priscilla D. A. M. Heijnen Linda Beckers Myrthe den Toom Marion J. J. Gijbels Louis Boon Christian Weber Helga E. de Vries Gerry A. F. Nicolaes Christine D. Dijkstra Gijs Kooij Esther Lutgens Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation Journal of Neuroinflammation Multiple sclerosis EAE Co-stimulation Monocytes Inflammation |
| title | Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation |
| title_full | Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation |
| title_fullStr | Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation |
| title_full_unstemmed | Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation |
| title_short | Inhibition of CD40-TRAF6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation |
| title_sort | inhibition of cd40 traf6 interactions by the small molecule inhibitor 6877002 reduces neuroinflammation |
| topic | Multiple sclerosis EAE Co-stimulation Monocytes Inflammation |
| url | http://link.springer.com/article/10.1186/s12974-017-0875-9 |
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