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Nat Commun. 2017 Oct 27;8(1):1164. doi: 10.1038/s41467-017-01283-z.

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

Author information

1
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.
2
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
3
Division of Brain Sciences, Imperial College London, Burlington Danes Building Du Cane Road, London, W12 0NN, UK.
4
Institute of Experimental Medicine ASCR and Charles University in Prague, Department of Neuroscience, Videnská 1083, Prague 4, 142 20, Czech Republic.
5
Sobell Department of Motor Neuroscience & Movement Disorders, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
6
UK Dementia Research Institute at UCL, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK.
7
Waisman Center, University of Wisconsin, 1500 Highland Avenue, Madison, WI, 53705, USA.
8
Department of Neuroinflammation, UCL Institute of Neurology, University College London, London, WC1N 1PJ, UK.
9
Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, WC1N 3BG, UK. rickie.patani@ucl.ac.uk.
10
The Francis Crick Institute, 1 Midland Road, London, NW1 1AT, UK. rickie.patani@ucl.ac.uk.
11
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. AL291@cam.ac.uk.
12
Addenbrooke's Hospital, Cambridge University Hospitals, Hills Road, Cambridge, CB2 0QQ, UK. AL291@cam.ac.uk.

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.

PMID:
29079839
PMCID:
PMC5660125
DOI:
10.1038/s41467-017-01283-z
[Indexed for MEDLINE]
Free PMC Article

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