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, András Lakatos

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Article number1164
Number of pages17
JournalNature Communications
Volume8
Issue number1
DOIs
Publication statusPublished - 27 Oct 2017

Keywords

  • amyotrophic lateral sclerosis
  • animals
  • anti-inflammatory agents
  • astrocytes
  • axons
  • cells
  • disease models
  • humans
  • inflammation
  • iInterleukin-6
  • male
  • mice
  • inbred C57BL
  • motor neurons
  • neurons
  • neuroprotection
  • receptor
  • STAT3 transcription factor
  • sciatic nerve
  • signal transduction
  • transcriptome
  • cytology

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