Figure 8

Proposed model of fibronectin aggregation by astrocytes. (a,b) Schematic representation of fibronectin fibrillogenesis^{46,47,48,49,62,67}. Under normal circumstances, fibronectin molecules bind primarily at the astrocyte surface to integrin α5β1, and to a lesser extent integrin αvβ3 (a). Fibronectin binding to the astrocyte surface unfolds fibronectin that allows self-association of fibronectin molecules to from a fibril matrix (b). (c,d) Schematic representation of fibronectin aggregation. Upon exposure to a pro-inflammatory environment, as present in MS lesions, relatively more EIIIA/EDA^pos-fibronectin than EIIIB/EDB^pos-fibronectin is produced. (c) This results in enhanced binding to integrin α5β1, reduced binding to integrin αvβ3, and impartial unfolding of fibronectin. (c) Upon a second-hit with a TLR3 agonist, the binding of fibronectin to the astrocyte surface is reduced, resulting in detachment (1) and refolding (2) of the fibronectin multimers in aggregates. (d) Notably, when EIIIA/EDA^pos-fibronectin levels are already high, fibronectin aggregates may be formed without prior exposure to pro-inflammatory cytokines (b,d). (e) Description of the used elements and symbols.