In the central nervous system (CNS), glia are key for maintaining tissue homeostasis. They function to support numerous processes including neurogenesis and neuronal survival, neural transmission, and immune surveillance. They also play a role in the initiation and progression of neuroinflammation and neurodegenerative disease. Astrocytes, the most abundant glial cell in the CNS, become activated in response to many insults, such as trauma, stroke, or neurodegenerative disease.1 Astrogliosis appears to be a complicated process as research is showing that the phenotype of reactive astrocytes may be defined by the injury type. Zamanian, J.L. et al., from the lab of Dr. Ben Barres at Stanford University School of Medicine, previously reported that two different reactive astrocyte phenotypes, which they termed A1 and A2, were present following systemic LPS administration and transient ischemia, respectively. The A1 astrocytes were believed to be toxic as they upregulated the expression of genes that are harmful to synapses (e.g. complement cascade genes), while the A2 astrocytes were protective as they expressed increased levels of neurotrophic factors and cytokines.2 The Barres lab continued to characterize these different astrocyte phenotypes. In a previous blog post, we reviewed a paper published earlier this year from Liddelow, S.A. et al. that reported the induction of A1 astrocytes by activated microglia. The authors found that activated microglia secrete IL-1 alpha, TNF, and C1q, which work together to induce neurotoxic astrocytes. Additionally, they showed that these A1 astrocytes can stimulate cell death of a variety of neural cell types.3
Now, a recent article in Nature Communications by Tyzack, G.E. et al. reports that neuronal Ephrin Type-B Receptor 1 (EphB1) induces the protective phenotype in astrocytes. These authors showed that injury to spinal motor neurons (SMN) via a unilateral facial axotomy increased the expression of EphB1 and its binding partner, Ephrin-B1, in injured neurons and neighboring astrocytes, respectively. Additionally, neuronal injury increased the levels of phosphorylated STAT3 (Y705) in astrocytes, a key regulator of astrogliosis.4 The authors then showed that treating cultured astrocytes with EphB1 increased the amount of phosphorylated STAT3 (Y705) detected in their nucleus, and transfection with an Ephrin-B1 siRNA prevented this effect. These results suggest that EphB1 induces STAT3 activation in astrocytes through Ephrin-B1 reverse signaling. The authors also showed that STAT3 activation was accompanied by the induction of astrocyte activation, as measured by morphological changes of cytoskeletal proteins and increased GFAP expression. The reactive astrocyte phenotype induced by neuronal EphB1 appeared to be neuroprotective as EphB1 treatment upregulated the expression of genes involved in immune-modulatory and anti-inflammatory processes. Furthermore, conditioned medium from cultured astrocytes treated with EphB1 partially blocked the toxic effect of increased extracellular glutamate levels on cultured SMN. Again, this effect appears to be dependent on Ephrin-B1 reverse signaling as conditioned medium from cultured astrocytes transfected with Ephrin-B1 siRNA prior to EphB1 treatment did not rescue SMN from glutamate toxicity.5
Tyzack G.E. et al. then wanted to determine the role of the EphB1 - Ephrin-B1 - STAT3 signaling pathway in amyotrophic lateral sclerosis (ALS). The authors showed that neuronal injury in SOD1G93A-ALS mice did not induce STAT3 activation in astrocytes. A similar response was seen in cultured human astrocytes that were derived from induced pluripotent stem cells (hiPSC-astrocytes) from SOD1D90A ALS patients. STAT3 was not activated in these hiPSC-astrocytes following stimulation with EphB1. Furthermore, the authors saw that gene expression associated with the activation of neuroprotective astrocytes was altered in hiPSC-astrocytes. They detected a decrease in the expression of genes associated with the EphB1 pathway and an increase in the expression of proinflammatory genes. The authors hypothesize from these results that EphB1 is a signal from injured neurons that triggers an early astrocyte response in attempt to promote tissue repair, and that this neuroprotective astrocytic response is impaired in ALS. In addition, the EphB1 - Ephrin-B1 - STAT3 pathway may represent a new target for the treatment of ALS and other neurodegenerative diseases.5
Read the full article at Nature Communications.
1. Liddelow, S.A. and B.A. Barres (2017) Immunity 46:957.
2. Zamanian, J.L. et al. (2012) J. Neurosci. 32:6391.
3. Liddelow, S.A. et al. (2017) Nature 541:481.
4. Herrmann, J.E. et al. (2008) J. Neurosci. 28:7231.
5. Tyzack, G.E. et al. (2017) Nat. Commun. 8:1164.