Astrocyte responses to neuronal injury may be beneficial or detrimental to neuronal recovery, but the mechanisms that determine these different responses are poorly understood. Here we show that ephrin type-B receptor 1 (EphB1) is upregulated in injured motor neurons, which in turn can activate astrocytes through ephrin-B1-mediated stimulation of signal transducer and activator of transcription-3 (STAT3). Transcriptional analysis shows that EphB1 induces a protective and anti-inflammatory signature in astrocytes, partially linked to the STAT3 network. This is distinct from the response evoked by interleukin (IL)-6 that is known to induce both pro inflammatory and anti-inflammatory processes. Finally, we demonstrate that the EphB1-ephrin-B1 pathway is disrupted in human stem cell derived astrocyte and mouse models of amyotrophic lateral sclerosis (ALS). Our work identifies an early neuronal help-me signal that activates a neuroprotective astrocytic response, which fails in ALS, and therefore represents an attractive therapeutic target.

Department of Molecular Neuroscience UCL Institute of Neurology University College London London WC1N 3BG UK

Department of Molecular Neuroscience UCL Institute of Neurology University College London London WC1N 3BG UK The Francis Crick Institute 1 Midland Road London NW1 1AT UK

Department of Neuroinflammation UCL Institute of Neurology University College London London WC1N 1PJ UK

Division of Brain Sciences Imperial College London Burlington Danes Building Du Cane Road London W12 0NN UK

Institute of Experimental Medicine ASCR and Charles University Prague Department of Neuroscience Videnská 1083 Prague 4 142 20 Czech Republic

John van Geest Centre for Brain Repair Department of Clinical Neurosciences University of Cambridge E D Adrian Building Forvie Site Robinson Way Cambridge CB2 0PY UK

John van Geest Centre for Brain Repair Department of Clinical Neurosciences University of Cambridge E D Adrian Building Forvie Site Robinson Way Cambridge CB2 0PY UK Addenbrooke's Hospital Cambridge University Hospitals Hills Road Cambridge CB2 0QQ UK

John van Geest Centre for Brain Repair Department of Clinical Neurosciences University of Cambridge E D Adrian Building Forvie Site Robinson Way Cambridge CB2 0PY UK Department of Molecular Neuroscience UCL Institute of Neurology University College London London WC1N 3BG UK

Sobell Department of Motor Neuroscience and Movement Disorders UCL Institute of Neurology University College London London WC1N 3BG UK

Sobell Department of Motor Neuroscience and Movement Disorders UCL Institute of Neurology University College London London WC1N 3BG UK UK Dementia Research Institute at UCL UCL Institute of Neurology University College London London WC1N 3BG UK

Waisman Center University of Wisconsin 1500 Highland Avenue Madison WI 53705 USA

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