alpha(V)beta(3) Integrin regulates astrocyte reactivity

Background: Neuroinflammation involves cytokine release, astrocyte reactivity and migration. Neuronal Thy-1 promotes DITNC1 astrocyte migration by engaging alpha(V)beta(3) 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 alpha(V)beta(3) Integrin, Syndecan-4, P2X7R, Pannexin-1, Connexin-43, GFAP, and iNOS were observed in TNF-treated astrocytes. Silencing of beta(3) Integrin prior to TNF treatment prevented Thy-1-induced migration, while beta(3) 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 alpha(V)beta(3) Integrin and other proteins, astrocyte reactivity, and Thy-1 responsiveness. Importantly, ectopic control of beta(3) Integrin levels modulates these responses regardless of inflammation.ONDECYT 3140460 1150744 1130250 1170925 1140301 3140471 3170645 CONICYT 21090323 21130008 CONICYT-FONDAP 15130011 Swiss National Science Foundation 310030_156961 Anillo ACT-1114 DRI USA 2013-0030 ATA 2014-F-03