Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy.
Ph.D. Program in Neuroscience and Education, DISCUM, University of Foggia, 71121, Foggia, Italy.
J Neuroimmune Pharmacol. 2022 Dec;17(3-4):427-436. doi: 10.1007/s11481-021-10016-5. Epub 2021 Oct 2.
Disruption of the blood brain barrier (BBB) is a common event in several neurological diseases and in particular, in multiple sclerosis (MS), it contributes to the infiltration of the central nervous system by peripheral inflammatory cells. Sphingosine-1-phosphate (S1P) is a bioactive molecule with pleiotropic effects. Agonists of S1P receptors such as fingolimod and siponimod (BAF-312) are in clinical practice for MS and have been shown to preserve BBB function in inflammatory conditions. Using an in vitro BBB model of endothelial-astrocytes co-culture exposed to an inflammatory insult (tumor necrosis factor-α and interferon-γ; T&I), we show that BAF-312 reduced the migration of peripheral blood mononuclear cells (PBMCs) through the endothelial layer, only in the presence of astrocytes. This effect was accompanied by decreased expression of the adhesion molecule ICAM-1. BAF-312 also reduced the activation of astrocytes, by controlling NF-kB and NLRP3 induction and preventing the increase of proinflammatory cytokine and chemokines. Reduction of CCL2 by BAF-312 may be responsible for the observed effects and, accordingly, addition of exogenous CCL2 was able to counteract BAF-312 effects and rescued T&I responses on PBMC migration, ICAM-1 expression and astrocyte activation. The present results further point out BAF-312 effects on BBB properties, suggesting also the key role of astrocytes in mediating drug effects on endothelial function.
血脑屏障（BBB）的破坏是几种神经疾病中的常见事件，特别是在多发性硬化症（MS）中，它有助于外周炎症细胞渗透到中枢神经系统。鞘氨醇-1-磷酸（S1P）是一种具有多种作用的生物活性分子。S1P 受体激动剂，如 fingolimod 和 siponimod（BAF-312），用于 MS 的临床实践中，并已被证明在炎症条件下可维持 BBB 功能。我们使用暴露于炎症刺激（肿瘤坏死因子-α和干扰素-γ；T&I）的内皮-星形胶质细胞共培养体外 BBB 模型，表明 BAF-312 仅在星形胶质细胞存在的情况下，减少外周血单核细胞（PBMC）穿过内皮层的迁移。这种作用伴随着粘附分子 ICAM-1 的表达减少。BAF-312 还通过控制 NF-kB 和 NLRP3 的诱导以及防止促炎细胞因子和趋化因子的增加来减少星形胶质细胞的激活。BAF-312 减少 CCL2 的表达可能是观察到的作用的原因，因此，添加外源性 CCL2 能够抵消 BAF-312 的作用，并挽救 T&I 对 PBMC 迁移、ICAM-1 表达和星形胶质细胞激活的反应。这些结果进一步指出了 BAF-312 对 BBB 特性的作用，也表明星形胶质细胞在介导药物对内皮功能的作用方面具有关键作用。
