α_Vβ₃ Integrin regulates astrocyte reactivity

Background: Neuroinflammation involves cytokine release, astrocyte reactivity and migration. Neuronal Thy-1 promotes DITNC1 astrocyte migration by engaging α_Vβ₃ Integrin and Syndecan-4. Primary astrocytes express low levels of these receptors and are unresponsive to Thy-1; thus, inflammation and astrocyte reactivity might be necessary for Thy-1-induced responses. Methods: Wild-type rat astrocytes (TNF-activated) or from human SOD1^G93A transgenic mice (a neurodegenerative disease model) were used to evaluate cell migration, Thy-1 receptor levels, signaling molecules, and reactivity markers. Results: Thy-1 induced astrocyte migration only after TNF priming. Increased expression of α_Vβ₃ Integrin, Syndecan-4, P2X7R, Pannexin-1, Connexin-43, GFAP, and iNOS were observed in TNF-treated astrocytes. Silencing of β₃ Integrin prior to TNF treatment prevented Thy-1-induced migration, while β₃ Integrin over-expression was sufficient to induce astrocyte reactivity and allow Thy-1-induced migration. Finally, hSOD1^G93A astrocytes behave as TNF-treated astrocytes since they were reactive and responsive to Thy-1. Conclusions: Therefore, inflammation induces expression of α_Vβ₃ Integrin and other proteins, astrocyte reactivity, and Thy-1 responsiveness. Importantly, ectopic control of β₃ Integrin levels modulates these responses regardless of inflammation.