The JAK2-STAT3 pathway is necessary and sufficient to induce reactivity in astrocytes

International audienceAstrocyte reactivity is a hallmark of neurological diseases. This response has been observed for over a century; yet, its functional consequences are still unclear, and the signaling cascades that control reactive astrocytes are not established. Several pathways are classically associated with astrocyte reactivity but their direct contribution is often not demonstrated or the reactive phenotype characterization is limited. Here, we used viral vectors targeting astrocytes to express elements or reporter systems of the JAK2-STAT3 pathway in several mouse models of neurodegenerative diseases (ND) in vivo. To explore the involvement of this cascade in astrocyte reactivity, we performed histological, biochemical analysis as well as astrocyte-specific transcriptomics. We found that STAT3 accumulated in the nucleus of reactive astrocytes in multiple animal models of ND. We developed a viral vector-based reporter system to monitor STAT3 activation in situ. Using this STAT3-reporter in selected murine models of ND, we confirmed that the JAK-STAT3 pathway is activated in reactive astrocytes. Expression of the pathway-specific inhibitor SOCS3 by viral gene transfer, prevented reactivity in mouse models of ND. SOCS3-expressing astrocytes expressed low levels of GFAP and vimentin, recovered a normal morphology and displayed a transcriptional profile of resting astrocytes. Mirror experiments were performed by overexpressing a constitutively active form of JAK2 (JAK2ca) in astrocytes of WT mice to activate the JAK2-STAT3 pathway in the absence of any pathological context. JAK2ca expression in striatal and hippocampal astrocytes activated STAT3, as demonstrated by an increased activity of the STAT3-reporter, enhanced STAT3 phosphorylation and nuclear accumulation. JAK2ca-expressing astrocytes were hypertrophic and they overexpressed GFAP along with many transcripts characteristics of reactive astrocytes. Our results show that the JAK-STAT3 pathway is necessary and sufficient for astrocyte reactivity in various disease contexts. This core cascade can be targeted to modulate reactive astrocytes and better understand their roles in ND