G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration

Degos, Vincent; Peineau, Stéphane; Nijboer, Cora H.; Kaindl, Angela M.; Sigaut, Stéphanie; Favrais, Géraldine; Plaisant, Frank; Teissier, Natacha; Gouadon, Elodie; Lombet, Alain; Saliba, Élie; Collingridge, Graham L.; Maze, Mervyn; Nicoletti, Ferdinando; Heijnen, Cobi J.; Mantz, Jean; Kavelaars, Annemieke; Gressèns, Pierre

doi:10.1002/ana.23868

Cited by 48 publications

(37 citation statements)

References 54 publications

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“…pression of IL-23 (a key factor for T H 17 cell differentiation), TNF␣, and iNOS mRNA (Ghoreschi et al, 2010). This analysis showed that neither pFTY720 nor S1P (up to 10 M) suppressed microglial activation directly (Fig.…”

Section: Fty720 Lacks Direct Inhibitory Effects On Microgliamentioning

confidence: 85%

“…Growing evidence indicates that perinatal inflammation exacerbates HI and excitotoxic lesions, causing greater brain damage in neonates (Dommergues et al, 2000;Dammann et al, 2002;Degos et al, 2013). Consequently, preclinical and clinical studies both indicate that inflammation-sensitized HI brain injury is less responsive to therapeutic hypothermia than pure-HI injury in neonates (Wintermark et al, 2010;Osredkar et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

“…However, it has been reported that chorioamnionitis induces circulating CD45RO-positive (CD45RO ϩ ) effector/ memory T-cells associated with brain damage in preterm neonates (Duggan et al, 2001). Because the traditional T-helper 1 (T H 1) or T H 2 cells are yet to mature in neonates (Sharma et al, 2012), we hypothesized that the early-onset active T-cells after infection/HI injury may be T H 17-like lymphocytes that have a high propensity to induce autoimmune and inflammatory disorders (Korn et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

“…This hypothesis is in accord with recent findings in rhesus macaques showing that experimental chorioamnionitis alters the regulatory T-cell/L-17 balance (Kallapur et al, 2013). Furthermore, several critical factors for T H 17-lymphocyte differentiation, including interleukin-6 (IL-6) and IL-1␤, are induced by neonatal HI injury (Bettelli et al, 2006;Ghoreschi et al, 2010). If this hypothesis is accurate, inflammation-sensitized neonatal HI brain injury may be treated by systemic administration of FTY720 (fingolimod), a sphingosine-1-phosphate receptor (S1PR) agonist that prevents lymphocytes from exiting the lymph nodes and reaching the target organs .…”

Section: Introductionmentioning

confidence: 99%

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Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

et al. 2014

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Section: Fty720 Lacks Direct Inhibitory Effects On Microgliamentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

et al. 2014

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“…On the other hand, it has been reported that activation of kainite receptors by culturing oligodendrocytes with as little as 10 μM glutamate sensitizes the oligodendrocytes to complement attack and lysis (Alberdi et al, 2006). Glutamate levels are increased in CNS lesions during MS (Pitt et al, 2003;Pampliega et al, 2011) and other CNS inflammatory situations (Erhardt et al, 2013;Degos et al, 2013). Therefore, it might be expected that oligodendrocytes in or near inflammatory loci could become more sensitized to antibody mediated attack than oligodendrocytes in other parts of the brain.…”

Section: Principal Findings Of the Thesismentioning

confidence: 99%

Development of a simple in vitro mature mixed glial model to investigate differential expression of cell markers on glial cells and their potential as targets in multiple sclerosis

Beasley¹

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Autoantibodies are present in many patients with demyelinating diseases and have been shown to have pathogenic potential in the case of people with neuromyelitis optica (NMO). However, it is still debated whether antibodies that are present in people with multiple sclerosis (MS) are pathogenic. There are multiple different mechanisms by which autoantibodies could exert their effects in MS, and they could potentially target any cell/structure within the central nervous system (CNS), although the focus of antibody studies in MS has been almost solely on myelin antigens. Recently, however, some evidence has suggested that astrocytes could also be targeted in MS. Therefore, there is a need for a simple but robust in vitro model to allow the testing of antibodies against oligodendrocytes and astrocytes. The hypothesis tested in this thesis is that a cell culture model containing a mixture of mature glial cells could be a useful model by which to test the pathogenicity of the antibodies from people with MS, and the antigens that they are targeting. In order to test this hypothesis, this thesis set out to develop a mature mixed glial cell culture model, to test whether one cell type could be killed without impacting on the health of the other cells, and to then use this model to test antibodies from people with MS.Chapter 2 describes the development of a rat neonatal-derived mature mixed glial culture. A method was developed that allowed cultures with a mixture of protoplasmic (type 1) and fibrous (type 2) astrocytes to grow alongside mature oligodendrocytes. This method did not rely on addition of extra growth factors, presumably due to the production of all factors required for growth of each cell type by the other cells in the mixed culture. Because of this co-dependence on the other cells in the mixed culture for growth and development, the next step was to test whether specific targeting (killing) of one cell would result in the death of the other cells in culture, as that could potentially interfere with the interpretation of results in later chapters investigating the effects of antibodies in patient sera. In Chapter 3, it was found that oligodendrocytes could be selectively targeted (using a commercially-available antibody against sulfatide) and the astrocytes remained unaffected. It proved to be more difficult to find a cell surface-expressed molecule that could target only astrocytes and not have ii adverse effects on oligodendrocytes. In the literature, one molecule that is generally considered to be expressed on astrocytes, but not oligodendrocytes, is GLAST, a glutamate transporter. Initial studies using an antibody against the intracellular N-terminus of GLAST confirmed that only astrocytes in culture were stained by this antibody. An antibody was therefore generated that was specific for an epitope of GLAST ) that is expressed on the extracellular side of the membrane. However, when this antibody was tested for its ability to kill astrocytes in culture, both oligodendrocytes and astrocytes were ...

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miR‐146b Protects the Perinatal Brain against Microglia‐Induced Hypomyelination

Bokobza

Joshi

Schang

et al. 2021

Annals of Neurology

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In the premature newborn, perinatal inflammation mediated by microglia contributes significantly to neurodevelopmental injuries including white matter injury (WMI). Brain inflammation alters development through neuroinflammatory processes mediated by activation of homeostatic microglia toward a pro-inflammatory and neurotoxic phenotype. Investigating immune regulators of microglial activation is crucial to find effective strategies to prevent and treat WMI. Methods: Ex vivo microglial cultures and a mouse model of WMI induced by perinatal inflammation (interleukin-1-beta [IL-1β] and postnatal days 1-5) were used to uncover and elucidate the role of microRNA-146b-5p in microglial activation and WMI. Results: A specific reduction in vivo in microglia of Dicer, a protein required for microRNAs maturation, reduces pro-inflammatory activation of microglia and prevents hypomyelination in our model of WMI. Microglial miRNome analysis in the WMI model identified miRNA-146b-5p as a candidate modulator of microglial activation. Ex vivo microglial cell culture treated with the pro-inflammatory stimulus lipopolysaccharide (LPS) led to overexpression of immunomodulatory miRNA-146b-5p but its drastic reduction in the microglial extracellular vesicles (EVs). To increase miRNA-146b-5p expression, we used a 3DNA nanocarrier to deliver synthetic miRNA-146b-5p specifically to microglia. Enhancing microglial miRNA-146b-5p overexpression significantly decreased LPS-induced activation, downregulated IRAK1, and restored miRNA-146b-5p levels in EVs. In our WMI model, 3DNA miRNA-146b-5p treatment significantly prevented microglial activation, hypomyelination, and cognitive defect induced by perinatal inflammation. Interpretations: These findings support that miRNA-146b-5p is a major regulator of microglia phenotype and could be targeted to reduce the incidence and the severity of perinatal brain injuries and their long-term consequences.

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G protein–coupled receptor kinase 2 and group I metabotropic glutamate receptors mediate inflammation‐induced sensitization to excitotoxic neurodegeneration

Cited by 48 publications

References 54 publications

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

Blocking Lymphocyte Trafficking with FTY720 Prevents Inflammation-Sensitized Hypoxic–Ischemic Brain Injury in Newborns

Development of a simple in vitro mature mixed glial model to investigate differential expression of cell markers on glial cells and their potential as targets in multiple sclerosis

miR‐146b Protects the Perinatal Brain against Microglia‐Induced Hypomyelination

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