Aarts Suzanne A B M, Seijkens Tom T P, Kusters Pascal J H, van der Pol Susanne M A, Zarzycka Barbara, Heijnen Priscilla D A M, Beckers Linda, den Toom Myrthe, Gijbels Marion J J, Boon Louis, Weber Christian, de Vries Helga E, Nicolaes Gerry A F, Dijkstra Christine D, Kooij Gijs, Lutgens Esther
Department of Medical Biochemistry, Subdivision of Experimental Vascular Biology, Academic Medical Center, University of Amsterdam, Meibergdreef 15, 1105 AZ, Amsterdam, The Netherlands.
Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands.
J Neuroinflammation. 2017 May 12;14(1):105. doi: 10.1186/s12974-017-0875-9.
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.
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).
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.
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.
白细胞流入中枢神经系统（CNS）是慢性神经炎症性疾病多发性硬化症（MS）的一个关键标志。因此，旨在抑制白细胞穿越血脑屏障（BBB）迁移的策略被视为对抗MS的有前景的治疗方法。由于CD40L-CD40二元组在髓样细胞中通过肿瘤坏死因子受体相关因子6（TRAF6）发出信号以诱导炎症和白细胞运输，我们探讨了特异性抑制CD40 - TRAF6相互作用可改善神经炎症的假说。
用人单核细胞与CD40 - TRAF6相互作用的小分子抑制剂（SMI）（6877002）处理，并测量其穿越人脑内皮细胞的迁移能力。为了在体内神经炎症条件下测试阻断CD40 - TRAF6的SMI的治疗潜力，将Lewis大鼠和C57BL / 6J小鼠进行急性实验性自身免疫性脑脊髓炎（EAE），并用SMI 6877002治疗6天（大鼠）或3周（小鼠）。
我们在此表明，CD40 - TRAF6相互作用的SMI（6877002）强烈且剂量依赖性地减少人单核细胞的跨内皮迁移。此外，经SMI处理后，单核细胞产生的活性氧（ROS）、肿瘤坏死因子（TNF）和白细胞介素（IL）-6减少，而抗炎细胞因子IL - 10的产生增加。在大鼠中，经SMI治疗后EAE的疾病严重程度降低，但在小鼠中未降低。然而，在两种模型中，显著减少的是浸润中枢神经系统的单核细胞衍生的巨噬细胞，而非T细胞。
总之，我们的结果表明，SMI介导的CD40 - TRAF6途径抑制使人类单核细胞向具有降低的跨内皮迁移能力的抗炎细胞倾斜，并且能够在神经炎症期间减少中枢神经系统浸润的单核细胞衍生的巨噬细胞，但对EAE疾病严重程度的改善作用极小。因此，我们得出结论，SMI介导的CD40 - TRAF6途径抑制可能是一种有益的治疗策略，可减少中枢神经系统中的单核细胞募集和巨噬细胞激活，并有可能用作对抗MS的联合治疗方法。
Zotero 插件
