1. Microglia Contributes to BAF-312 Effects on Blood-Brain Barrier Stability
- Author
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Simona Federica Spampinato, Giuseppe Costantino, Sara Merlo, Pier Luigi Canonico, and Maria Angela Sortino
- Subjects
Multiple Sclerosis ,CCL5 ,Tumor Necrosis Factor-alpha ,Endothelial Cells ,HMC3 cells ,Biochemistry ,Phosphates ,S1P1 ,barrier permeability ,claudin-5 ,endothelial cells ,siponimod ,CCR5 ,Blood-Brain Barrier ,Sphingosine ,Benzyl Compounds ,Azetidines ,Cytokines ,Humans ,Matrix Metalloproteinase 2 ,Microglia ,Molecular Biology - Abstract
Microglia, together with astrocytes and pericytes, cooperate to ensure blood–brain barrier (BBB) stability, modulating endothelial responses to inflammatory insults. Agonists of the sphingosine 1 phosphate (S1P) receptors, such as siponimod (BAF-312), are important pharmacological tools in multiple sclerosis and other inflammatory diseases. Modulation of S1P receptors may result in a reduced inflammatory response and increased BBB stability. An in vitro BBB model was reproduced using human-derived endothelial cells, astrocytes and microglia. Co-cultures were exposed to inflammatory cytokines (TNFα, 10 UI and IFNγ, 5 UI) in the presence of BAF-312 (100 nM), and the BBB properties and microglia role were evaluated. The drug facilitated microglial migration towards endothelial/astrocyte co-cultures, involving the activity of the metalloprotease 2 (MMP2). Microglia actively cooperated with astrocytes in the maintenance of endothelial barrier stability: in the triple co-culture, selective treatment of microglial cells with BAF-312 significantly prevented cytokines’ effects on the endothelial barrier. In conclusion, BAF-312, modulating S1P receptors in microglia, may contribute to the reinforcement of the endothelial barrier at the BBB, suggesting an additional effect of the drug in the treatment of multiple sclerosis.
- Published
- 2022