αVβ3 Integrin regulates astrocyte reactivity

Abstract

BackgroundNeuroinflammation involves cytokine release, astrocyte reactivity and migration. Neuronal Thy-1 promotes DITNC1 astrocyte migration by engaging αVβ3 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.MethodsWild-type rat astrocytes (TNF-activated) or from human SOD1G93A transgenic mice (a neurodegenerative disease model) were used to evaluate cell migration, Thy-1 receptor levels, signaling molecules, and reactivity markers.ResultsThy-1 induced astrocyte migration only after TNF priming. Increased expression of αVβ3 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, hSOD1G93A astrocytes behave as TNF-treated astrocytes since they were reactive and responsive to Thy-1.ConclusionsTherefore, inflammation induces expression of αVβ3 Integrin and other proteins, astrocyte reactivity, and Thy-1 responsiveness. Importantly, ectopic control of β3 Integrin levels modulates these responses regardless of inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12974-017-0968-5) contains supplementary material, which is available to authorized users.

Intracellular Ca2+ Increases and Connexin 43 Hemichannel Opening Are Necessary but Not Sufficient for Thy-1-Induced Astrocyte Migration

“…Primary astrocytes were obtained from 1–2-day-old wild-type rats (Wistar strain), as previously described [4]. Cultures were maintained in DMEM/F12 nutrient mixture (1:1), supplemented with 10% FBS and 1% penicillin/streptomycin.…”

The urokinase‐type plasminogen activator system as drug target in retinitis pigmentosa: New pre‐clinical evidence in the rd10 mouse model

“…49 The additional evidence that HIF-1α stabilization in the In addition, in cultured astrocytes, inflammation induces the expression of αvβ3 integrin that appears to regulate astrocyte reactivity. 50 In models of diabetic nephropathy, up-regulated levels of αvβ3 integrin and increased Rac-1 activity are associated with main inflammatory processes as demonstrated by ameliorative effects of systemic UPARANT administration. 21 In the diseased brain, activation of αvβ3 integrin promotes the release of inflammatory factors while its inhibition has been shown to reduce brain inflammatory reactions.…”

Thy1/CD90 Surface Glycoprotein: Sensor of the Microenvironment?

“…An example of how the environment can influence Thy-1/CD90 localization is provided by Ilic et al who, using biochemical assays, offer evidence that modification of a class of glycosphingolipids called gangliosides entails redistribution of Thy-1/CD90 in brain-derived neuronal membranes. In the neurological compartment, Thy-1/CD90 interacts with α v β 3 integrin on reactive astrocytes to promote astrocyte adhesion (Leyton et al, 2001;Hermosilla et al, 2008;Lagos-Cabre et al, 2017). An interesting question would be whether this more adhesive phenotype may contribute to manifestation of diseases associated with ganglioside deficiency (Sandhoff et al, 2018).…”