scholarly journals Notch1–STAT3–ETBR signaling axis controls reactive astrocyte proliferation after brain injury

2015 ◽  
Vol 112 (28) ◽  
pp. 8726-8731 ◽  
Author(s):  
Matthew D. LeComte ◽  
Issei S. Shimada ◽  
Casey Sherwin ◽  
Jeffrey L. Spees
Keyword(s):  
Brain Injury ◽  
Signaling Network ◽  
Reactive Astrocytes ◽  
Conditional Knockout ◽  
Reactive Astrocyte ◽  
Astrocyte Proliferation ◽  
Signaling Axis ◽  
Radial Glial ◽  
Transcription 3 ◽  
Notch1 Receptor

Defining the signaling network that controls reactive astrogliosis may provide novel treatment targets for patients with diverse CNS injuries and pathologies. We report that the radial glial cell antigen RC2 identifies the majority of proliferating glial fibrillary acidic protein-positive (GFAP+) reactive astrocytes after stroke. These cells highly expressed endothelin receptor type B (ETBR) and Jagged1, a Notch1 receptor ligand. To study signaling in adult reactive astrocytes, we developed a model based on reactive astrocyte-derived neural stem cells isolated from GFAP-CreER-Notch1 conditional knockout (cKO) mice. By loss- and gain-of-function studies and promoter activity assays, we found that Jagged1/Notch1 signaling increased ETBR expression indirectly by raising the level of phosphorylated signal transducer and activator of transcription 3 (STAT3), a previously unidentified EDNRB transcriptional activator. Similar to inducible transgenic GFAP-CreER-Notch1-cKO mice, GFAP-CreER-ETBR-cKO mice exhibited a defect in reactive astrocyte proliferation after cerebral ischemia. Our results indicate that the Notch1–STAT3–ETBR axis connects a signaling network that promotes reactive astrocyte proliferation after brain injury.

scholarly journals Notch1 and Galectin-3 Modulate Cortical Reactive Astrocyte Response After Brain Injury

2021 ◽  
Vol 9 ◽  
Author(s):  
Tais Novaki Ribeiro ◽  
Lina Maria Delgado-García ◽  
Marimelia A. Porcionatto
Keyword(s):  
Brain Injury ◽  
Notch Signaling ◽  
Nuclear Translocation ◽  
Reactive Astrocytes ◽  
Reactive Astrocyte ◽  
Notch1 Signaling ◽  
Cortical Astrocytes ◽  
Lesion Core ◽  
Galectin 3

After a brain lesion, highly specialized cortical astrocytes react, supporting the closure or replacement of the damaged tissue, but fail to regulate neural plasticity. Growing evidence indicates that repair response leads astrocytes to reprogram, acquiring a partially restricted regenerative phenotype in vivo and neural stem cells (NSC) hallmarks in vitro. However, the molecular factors involved in astrocyte reactivity, the reparative response, and their relation to adult neurogenesis are poorly understood and remain an area of intense investigation in regenerative medicine. In this context, we addressed the role of Notch1 signaling and the effect of Galectin-3 (Gal3) as underlying molecular candidates involved in cortical astrocyte response to injury. Notch signaling is part of a specific neurogenic microenvironment that maintains NSC and neural progenitors, and Gal3 has a preferential spatial distribution across the cortex and has a central role in the proliferative capacity of reactive astrocytes. We report that in vitro scratch-reactivated cortical astrocytes from C57Bl/6J neonatal mice present nuclear Notch1 intracellular domain (NICD1), indicating Notch1 activation. Colocalization analysis revealed a subpopulation of reactive astrocytes at the lesion border with colocalized NICD1/Jagged1 complexes compared with astrocytes located far from the border. Moreover, we found that Gal3 increased intracellularly, in contrast to its extracellular localization in non-reactive astrocytes, and NICD1/Gal3 pattern distribution shifted from diffuse to vesicular upon astrocyte reactivation. In vitro, Gal3–/– reactive astrocytes showed abolished Notch1 signaling at the lesion core. Notch1 receptor, its ligands (Jagged1 and Delta-like1), and Hes5 target gene were upregulated in C57Bl/6J reactive astrocytes, but not in Gal3–/– reactive astrocytes. Finally, we report that Gal3–/– mice submitted to a traumatic brain injury model in the somatosensory cortex presented a disrupted response characterized by the reduced number of GFAP reactive astrocytes, with smaller cell body perimeter and decreased NICD1 presence at the lesion core. These results suggest that Gal3 might be essential to the proper activation of Notch signaling, facilitating the cleavage of Notch1 and nuclear translocation of NICD1 into the nucleus of reactive cortical astrocytes. Additionally, we hypothesize that reactive astrocyte response could be dependent on Notch1/Jagged1-Hes5 signaling activation following brain injury.

scholarly journals Endothelin ETB Receptor-Mediated Astrocytic Activation: Pathological Roles in Brain Disorders

2021 ◽  
Vol 22 (9) ◽  
pp. 4333
Author(s):  
Yutaka Koyama
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neurotrophic Factors ◽  
Drug Target ◽  
Therapeutic Strategy ◽  
Reactive Astrocytes ◽  
Brain Disorders ◽  
Etb Receptor ◽  
Target Molecules ◽  
Endothelin B

In brain disorders, reactive astrocytes, which are characterized by hypertrophy of the cell body and proliferative properties, are commonly observed. As reactive astrocytes are involved in the pathogenesis of several brain disorders, the control of astrocytic function has been proposed as a therapeutic strategy, and target molecules to effectively control astrocytic functions have been investigated. The production of brain endothelin-1 (ET-1), which increases in brain disorders, is involved in the pathophysiological response of the nervous system. Endothelin B (ETB) receptors are highly expressed in reactive astrocytes and are upregulated by brain injury. Activation of astrocyte ETB receptors promotes the induction of reactive astrocytes. In addition, the production of various astrocyte-derived factors, including neurotrophic factors and vascular permeability regulators, is regulated by ETB receptors. In animal models of Alzheimer’s disease, brain ischemia, neuropathic pain, and traumatic brain injury, ETB-receptor-mediated regulation of astrocytic activation has been reported to improve brain disorders. Therefore, the astrocytic ETB receptor is expected to be a promising drug target to improve several brain disorders. This article reviews the roles of ETB receptors in astrocytic activation and discusses its possible applications in the treatment of brain disorders.

scholarly journals Blocking microglial activation of reactive astrocytes is neuroprotective in models of Alzheimer’s disease

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Jong-Sung Park ◽  
Tae-In Kam ◽  
Saebom Lee ◽  
Hyejin Park ◽  
Yumin Oh ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Neurodegenerative Disorders ◽  
Critical Role ◽  
Subcutaneous Administration ◽  
Reactive Astrocytes ◽  
Reactive Astrocyte ◽  
Spatial Learning And Memory ◽  
Neuronal Viability ◽  
Age Related

AbstractAlzheimer’s disease (AD) is the most common cause of age-related dementia. Increasing evidence suggests that neuroinflammation mediated by microglia and astrocytes contributes to disease progression and severity in AD and other neurodegenerative disorders. During AD progression, resident microglia undergo proinflammatory activation, resulting in an increased capacity to convert resting astrocytes to reactive astrocytes. Therefore, microglia are a major therapeutic target for AD and blocking microglia-astrocyte activation could limit neurodegeneration in AD. Here we report that NLY01, an engineered exedin-4, glucagon-like peptide-1 receptor (GLP-1R) agonist, selectively blocks β-amyloid (Aβ)-induced activation of microglia through GLP-1R activation and inhibits the formation of reactive astrocytes as well as preserves neurons in AD models. In two transgenic AD mouse models (5xFAD and 3xTg-AD), repeated subcutaneous administration of NLY01 blocked microglia-mediated reactive astrocyte conversion and preserved neuronal viability, resulting in improved spatial learning and memory. Our study indicates that the GLP-1 pathway plays a critical role in microglia-reactive astrocyte associated neuroinflammation in AD and the effects of NLY01 are primarily mediated through a direct action on Aβ-induced GLP-1R+ microglia, contributing to the inhibition of astrocyte reactivity. These results show that targeting upregulated GLP-1R in microglia is a viable therapy for AD and other neurodegenerative disorders.

Death receptors on reactive astrocytes

Neurology ◽  
2003 ◽  
Vol 60 (4) ◽  
pp. 548-554 ◽  
Author(s):  
Pierre-Yves Dietrich ◽  
Paul R. Walker ◽  
Philippe Saas
Keyword(s):  
Brain Injury ◽  
Immune Responses ◽  
Death Receptors ◽  
Reactive Astrocytes ◽  
Brain Inflammation ◽  
Fine Tuning ◽  
Immune Mediated ◽  
Anti Inflammatory ◽  
The Brain

Immune responses protect the CNS against pathogens. However, the fact that there is little dispensable tissue in the brain makes regulation necessary to avoid disastrous immune-mediated damage. Astrocytes respond vigorously to any brain injury (e.g., tumor, stroke, AD, MS, HIV) and are postulated to play an important role in the fine tuning of brain inflammation. The authors propose that astrocytes use death receptors to modulate pro- and anti-inflammatory effects.

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