Inflammation Promotes a Conversion of Astrocytes into Neural Progenitor Cells via NF-κB Activation

Gabel, Sébastien; Koncina, Eric; Dorban, Gauthier; Heurtaux, Tony; Birck, Cindy; Glaab, Enrico; Michelucci, Alessandro; Heuschling, Paul; Grandbarbe, Luc

doi:10.1007/s12035-015-9428-3

Cited by 55 publications

(57 citation statements)

References 53 publications

(67 reference statements)

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“…The protective effects on oligodendrocytes and inhibition of reactive astrocyte proliferation/reactive gliosis, promoted via NF‐κB activation (Gabel et al. ), achieved functional recovery of EAE clinical symptoms in all treated groups.…”

Section: Discussionmentioning

confidence: 97%

Role of C16, angiopoietin‐1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis

et al. 2016

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Multiple sclerosis (MS) is a chronic neurological disorder that affects the central nervous system (CNS), and results in CNS inflammation and damage to myelin. In this study, we examined the possible synergistic effects of C16, angiopoietin-1 (Ang-1) and regeneration gene protein 2 (Reg-2) in alleviating inflammation in an acute experimental autoimmune encephalomyelitis (EAE) model. We employed multiple histological, morphological and iconographic assays to examine the effect of those drugs on disease onset, clinical scores and behavioral deficits. Our results demonstrated that triple combination therapy was more efficient than the monotherapy in EAE treatment. The triple therapy significantly delayed the onset of motor symptoms, reduced disease severity, attenuated inflammatory cell infiltration and suppressed the secretion of proinflammatory cytokines. Additionally, treatment increased anti-inflammatory cytokines expression, inhibited reactive astrocytes proliferation, reduced demyelination and axonal loss, and finally reduced the neural death. Specifically, Reg-2 administration rescued oligodendrocytes and neuronal axons mainly by direct neurotrophic effects, while C16+Ang-1 (C+A) mainly improved the inflammatory milieu. In conclusion, our study suggests a possible synergistic effect through targeting a variety of pathways in relieving the clinical symptoms of inflammation in acute EAE model. Therefore, using molecules that target different molecular pathways can be beneficial for exploring novel therapeutic approaches for MS treatment.

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Section: Discussionmentioning

confidence: 97%

Role of C16, angiopoietin‐1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis

et al. 2016

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“…Astroglia may induce neurogenesis from adult stem cells . Inflammation‐induced NF‐κB activation promotes the conversion of astrocytes into neural progenitor cells . Proliferation results in an increase in the number of astrocytes which must not be mistaken for the mere enhancement of GFAP expression in already existent astrocytes.…”

Section: Reactive Astrogliosismentioning

confidence: 99%

Diversity of astroglial responses across human neurodegenerative disorders and brain aging

Ferrer

2017

Brain Pathology

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Astrogliopathy refers to alterations of astrocytes occurring in diseases of the nervous system, and it implies the involvement of astrocytes as key elements in the pathogenesis and pathology of diseases and injuries of the central nervous system. Reactive astrocytosis refers to the response of astrocytes to different insults to the nervous system, whereas astrocytopathy indicates hypertrophy, atrophy/degeneration and loss of function and pathological remodeling occurring as a primary cause of a disease or as a factor contributing to the development and progression of a particular disease. Reactive astrocytosis secondary to neuron loss and astrocytopathy due to intrinsic alterations of astrocytes occur in neurodegenerative diseases, overlap each other, and, together with astrocyte senescence, contribute to disease-specific astrogliopathy in aging and neurodegenerative diseases with abnormal protein aggregates in old age. In addition to the well-known increase in glial fibrillary acidic protein and other proteins in reactive astrocytes, astrocytopathy is evidenced by deposition of abnormal proteins such as β-amyloid, hyper-phosphorylated tau, abnormal α-synuclein, mutated huntingtin, phosphorylated TDP-43 and mutated SOD1, and PrP , in Alzheimer's disease, tauopathies, Lewy body diseases, Huntington's disease, amyotrophic lateral sclerosis and Creutzfeldt-Jakob disease, respectively. Astrocytopathy in these diseases can also be manifested by impaired glutamate transport; abnormal metabolism and release of neurotransmitters; altered potassium, calcium and water channels resulting in abnormal ion and water homeostasis; abnormal glucose metabolism; abnormal lipid and, particularly, cholesterol metabolism; increased oxidative damage and altered oxidative stress responses; increased production of cytokines and mediators of the inflammatory response; altered expression of connexins with deterioration of cell-to-cell networks and transfer of gliotransmitters; and worsening function of the blood brain barrier, among others. Increased knowledge of these aspects will permit a better understanding of brain aging and neurodegenerative diseases in old age as complex disorders in which neurons are not the only players.

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“…Surprisingly, we found that only 2 cytokines, namely IL-17D and IL33, co-upregulated with Cx43/GJA1 in spinal cord periplaque areas. Other inflammation-related genes comprised notably CD44 and CD200 that were both previously demonstrated on reactive astrocytes [37,38]. Finally, the GJA1/Cx43 module comprised several ECM-related genes that are expressed by …”

Section: A Unique Set Of Genes Co-upregulate With Cx43/gja1 In Periplmentioning

confidence: 85%

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

Nataf¹,

Barritault²,

Pays³

2017

Preprint

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Abstract:We previously reported that in multiple sclerosis (MS) patients with a progressive form of the disease, spinal cord periplaques extend distance away from plaque borders and are characterized by the co-occurrence of partial demyelination, astrocytosis and low-grade inflammation. However, transcriptomic analyses comparing periplaques to adjacent normal-appearing white matter (NAWM) areas did not allow providing a comprehensive view of molecular events in astrocytes vs oligodendrocytes. Here, we re-assessed our transcriptomic data with the aim of identifying functionally-relevant co-expression networks that would reflect astrocyte vs oligodendrocyte molecular signatures in periplaques. We identified an astrocytosis-related gene module comprising GFAP, the hub gene CX43/GJA1 and a set of transcripts forming a TGFB/SMAD1/SMAD2 genomic signature. Partial demyelination was characterized by a co-expression network which, besides myelin genes, comprised a highly significant number of translation/elongation-related genes. Interestingly, the main oligodendrocyte-related hub we identified was NDRG1, a gene previously shown to be specifically silenced in the NAWM of MS patients. This result indicated that NDRG1 down-regulation could be an important event in the process of periplaque partial demyelination. To establish a putative link between NDRG1 down-regulation and a cytokine/chemokine signature, we then sought to identify cytokine/chemokine genes whose mRNA levels inversely correlated with those of NDRG1. Following this approach we found 5 candidate immune-related genes whose up-regulation associated with NDRG1 down-regulation: TGFB1, PDGFC, . From these results we propose that in the spinal cord of MS patients with progressive forms of the disease, TGFB1 may Preprints (www.preprints.org) | NOT PEER-REVIEWED | Posted:

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Inflammation Promotes a Conversion of Astrocytes into Neural Progenitor Cells via NF-κB Activation

Cited by 55 publications

References 53 publications

Role of C16, angiopoietin‐1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis

Role of C16, angiopoietin‐1 and regeneration gene protein 2 in attenuating inflammation in an experimental rat model of autoimmune encephalomyelitis

Diversity of astroglial responses across human neurodegenerative disorders and brain aging

A Unique TGFB1-Driven Genomic Program Links Astrocytosis, Low-Grade Inflammation and Partial Demyelination in Periplaques of Spinal Cords from Progressive Multiple Sclerosis Patients

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