A neuroprotective astrocyte state is induced by neuronal signal EphB1 but fails in ALS models

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.This work has been funded by Medical Research Council (MR/P008658/1 for A.L.), the Walker Fund (A.L.), John van Geest Fund (A.L.) and the Wellcome Trust (101149/Z/13/A for R.P.). We also acknowledge the DPUK/MRC platform for provision of the Opera Phenix for high-throughput iPSC analysis and the support by the National Institute for Health Research University College London Hospitals Biomedical Research Centre. We are grateful for the support from the Grant Agency of the Czech Republic (GACR 17-21146 S, S.F.). Dr Christopher Sibley is supported by the Edmond Lilly Safra Fellowship, Dr Rickie Patani holds a Wellcome Trust Clinician Scientist Fellowship and Dr András Lakatos holds an MRC Clinician Scientist Fellowship