Astrocyte reactivity and neuroinflammation are hallmarks of CNS pathological conditions such as Alzheimer’s disease. However, the specific role of reactive astrocytes is still debated. This controversy may stem from the fact that most strategies used to modulate astrocyte reactivity and explore its contribution to disease outcomes have only limited specificity. Moreover, reactive astrocytes are now emerging as heterogeneous cells and all types of astrocyte reactivity may not be controlled efficiently by such strategies.Here, we used cell type-specific approaches in vivo and identified the JAK2-STAT3 pathway, as necessary and sufficient for the induction and maintenance of astrocyte reactivity. Modulation of this cascade by viral gene transfer in mouse astrocytes efficiently controlled several morphological and molecular features of reactivity. Inhibition of this pathway in mouse models of Alzheimer’s disease improved three key pathological hallmarks by reducing amyloid deposition, improving spatial learning and restoring synaptic deficits.In conclusion, the JAK2-STAT3 cascade operates as a master regulator of astrocyte reactivity in vivo. Its inhibition offers new therapeutic opportunities for Alzheimer’s disease.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0606-1) contains supplementary material, which is available to authorized users.

Astrocytes play multiple important roles in brain physiology. In pathological conditions, they become reactive, which is characterized by morphological changes and upregulation of intermediate filament proteins. Besides these descriptive hallmarks, astrocyte reactivity involves significant transcriptional and functional changes that are far from being fully understood. Most importantly, astrocyte reactivity seems to encompass multiple states, each having a specific influence on surrounding cells and disease progression. These diverse functional states of reactivity must be regulated by subtle signaling networks. Many signaling cascades have been associated with astrocyte reactivity, but among them, the JAK-STAT3 pathway is emerging as a central regulator. In this review, we aim (i) to show that the JAK-STAT3 pathway plays a key role in the control of astrocyte reactivity, (ii) to illustrate that STAT3 is a pleiotropic molecule operating multiple functions in reactive astrocytes, and (iii) to suggest that each specific functional state of reactivity is governed by complex molecular interactions within astrocytes, which converge on STAT3. More research is needed to precisely identify the signaling networks controlling the diverse states of astrocyte reactivity. Only then, we will be able to precisely delineate the therapeutic potential of reactive astrocytes in each neurological disease context.