Effecten van fibronectine aggregaten op gedrag en activatie van microglia in vitro, in relatie tot Multiple Sclerose’

Multiple Sclerosis is a neuroinflammatory disorder, involving damage to myelin and demyelination of axons. During an active episode, the blood-brain barrier is disrupted and transient influx of both plasma cells and proteins will occur. One of the plasma proteins is fibronectin. In addition to fibronectin from the plasma, fibronectin produced by astrocytes is present in the brain parenchyma, so called cellular fibronectin. Cellular fibronectine is only present when the brain parenchyma becomes damaged. Previous research has shown that in MS lesions cellular- and plasma fibronectin are able to aggragate, and that aggregates are hard to be removed. In vitro research has shown that stimulation of astrocytes with toll-like receptor 3 ligand Poly I:C causes aggregation of cellular and plasma fibronectin. These fibronectin aggregates inhibit remyelination, which will eventually lead to neurodegeneration. Microglia are the resident immune cells of the central nervous system. They may respond to the fibronectin aggregates and thus contribute to the inhibition of remyelination ultimately leading to neurodegeneration. It is unknown what the effects of cellular- and aggregated fibronectin are on microglial activation and behavior. Nitric-oxide production by microglia, and cell morphology demonstrated that aggregated fibronectin causes significant reduction in alternative activated microglia. Plasma fibronectin ellicits increased microglial phagocytosis, migration and proliferation. Aggregated fibronectin results in increased proliferation and phagocytosis rates. Cellular fibronectin shows a decrease in classical activation of microglia and reduces phagocytosis and migration activity. Our data suggest fibronectin influences the activation and the behavior of microglia in vitro. In MS, this would mean that fibronectin aggregates might incite microglia to a more intense inflammation, with more demyelination and because of sustained receptor stimulation cause delayed remyelination.