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

Giulia E. Tyzack, Claire E. Hall, Christopher R. Sibley, Tomasz Cymes, Serhiy Forostyak, Giulia Carlino, Ione F. Meyer, Giampietro Schiavo, Su-Chun Zhang, George M. Gibbons, Jia Newcombe, Rickie Patani () and András Lakatos ()
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Giulia E. Tyzack: University of Cambridge, E.D. Adrian Building
Claire E. Hall: University College London
Christopher R. Sibley: Burlington Danes Building Du Cane Road
Tomasz Cymes: University of Cambridge, E.D. Adrian Building
Serhiy Forostyak: Department of Neuroscience
Giulia Carlino: University College London
Ione F. Meyer: UCL Institute of Neurology, University College London
Giampietro Schiavo: UCL Institute of Neurology, University College London
Su-Chun Zhang: University of Wisconsin
George M. Gibbons: University of Cambridge, E.D. Adrian Building
Jia Newcombe: University College London
Rickie Patani: University College London
András Lakatos: University of Cambridge, E.D. Adrian Building

Nature Communications, 2017, vol. 8, issue 1, 1-17

Abstract: Abstract 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.

Date: 2017
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DOI: 10.1038/s41467-017-01283-z

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