Interleukin‐1β promotes oligodendrocyte death through glutamate excitotoxicity

Takahashi, Jennifer; Giuliani, Fabrizio; Power, Christopher; Imai, Yoshinori; Yong, V. Wee

doi:10.1002/ana.10519

Cited by 233 publications

(157 citation statements)

References 45 publications

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“…DAMP signaling then leads to the activation of caspase 1, which in turn cleaves pro-IL-1 into active IL-1β (Walsh et al, 2014a). Upon activation by IL-1β, astrocytes can release large amounts of innate immune inflammatory mediators including several complement cascade proteins; cytokines including tumor necrosis factor (TNF), IL-1β, IL-6; and chemokines with CC (cysteine-cysteine) and CXC (cysteine-other amino acids-cysteine) motifs including CCL2, CXCL1, CXCL10, and CXCL12 (Bezzi et al, 2001;Fischer et al, 2014;Johnstone et al, 1999;Marz et al, 1999;Olmos and Llado, 2014;Santello and Volterra, 2012;Takahashi et al, 2003a;Torres-Platas et al, 2014b;Xie et al, 2003). This state is also associated with impaired glutamate clearance and oxidative stress, both of which contribute to excitotoxicity Tilleux and Hermans, 2007;Zou and Crews, 2005).…”

Section: Immune Regulationmentioning

confidence: 99%

“…Although cell death from glutamate overactivation of AMPA/kainite receptors is of interest in the study of demyelinating disorders, toxicity from oligodendrocytic NMDA receptors might be of interest to psychiatry, as these receptors are located on the oligodendrocyte branches that are active myelin-synthesizing regions (Matute, 2006). Similar to astrocytes, increases in inflammatory cytokines such as TNF and IL-1β are known to impair glutamate buffering and clearance by oligodendrocyte EAATs, and trigger glutamate toxicity (Takahashi et al, 2003a;Takahashi et al, 2003b). Indeed, inhibition of the expression and functioning of glutamate transporters such as EAATs and xC-transporters in axonal tracts is sufficient to induce oligodendrocyte loss and demyelination, which undermines brain connectivity (Domercq et al, 2007;Evonuk et al, 2015).…”

Section: Oligodendrocytes and Glutamatementioning

confidence: 99%

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Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

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Increasing data indicate that inflammation and alterations in glutamate neurotransmission are two novel pathways to pathophysiology in mood disorders. The primary goal of this review is to illustrate how these two pathways may converge at the level of the glia to contribute to neuropsychiatric disease. We propose that a combination of failed clearance and exaggerated release of glutamate by glial cells during immune activation leads to glutamate increases and promotes aberrant extrasynaptic signaling through ionotropic and metabotropic glutamate receptors, ultimately resulting in synaptic dysfunction and loss. Furthermore, glutamate diffusion outside the synapse can lead to the loss of synaptic fidelity and specificity of neurotransmission, contributing to circuit dysfunction and behavioral pathology. This review examines the fundamental role of glia in the regulation of glutamate, followed by a description of the impact of inflammation on glial glutamate regulation at the cellular, molecular, and metabolic level. In addition, the role of these effects of inflammation on glia and glutamate in mood disorders will be discussed along with their translational implications.

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Section: Immune Regulationmentioning

confidence: 99%

Section: Oligodendrocytes and Glutamatementioning

confidence: 99%

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Haroon

Miller

Sanacora

2016

Neuropsychopharmacol

414

299

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“…26 Recent research indicates the possible role of glial TNFA and other cytokines in synaptic strength control at excitatory synapses 70 and apoptosis of oligodendrocytes through glutamate excitotoxicity. 71 This provides a different kind of mechanistic link to schizophrenia that would be compatible with the increasing genetic evidence for the glutamate hypothesis. 72,73 To date, no other association study of TNFA promoter polymorphisms with schizophrenia has analyzed haplotypes in extended pedigrees.…”

Section: Discussionmentioning

confidence: 80%

Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44

et al. 2004

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Using restriction fragment length polymorphism and pyrosequencing methods, we genotyped two TNFA gene promoter SNPs (ÀG308A, ÀG238A) and analyzed the haplotype structure in 24 Canadian families of primarily Celtic origin. Our results demonstrate that after correction for multiple testing based on simulations of 10 000 replicates of unlinked/unassociated data, there is evidence for association (P ¼ 0.026) of a specific haplotype (À308A, À238G) with schizophrenia and schizophrenia spectrum disorders with a family-based trimmed haplotype linkage disequilibrium test (Trimhap). Stratifying the 22 families with genome scan data by TNFA promoter haplotypes followed by reanalysis of linkage to schizophrenia throughout the genome, we identified few loci that exhibit a considerable increase in LOD/HLOD scores. A locus on chromosome 1q44 (D1S1609) demonstrated a significant increase (P ¼ 0.025) in LOD score from 0.15 to 3.01 with a broad definition of the schizophrenia phenotype and a dominant mode of inheritance. This result replicates a previously reported positive result of linkage of schizophrenia spectrum disorders to this area of the genome. We also illustrated that simulation studies are pivotal in evaluating the significance of results obtained with newer statistical methods, when multiple, but not independent, tests are performed, and when sample stratification is utilized to reduce the impact of heterogeneity or assess the interaction between loci.

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“…Both glutamate and ATP lead to calcium overload, which can trigger multiple intracellular pathways leading to cell demise [19,20]. In addition, cytokines such as tumor necrosis factor-α and interleukin (IL)-1β, which are up-regulated within minutes after SCI [21,22], can exacerbate excitotoxicity by impairing glutamate uptake [23].…”

Section: Early Mechanisms Of Ol Lossmentioning

confidence: 99%

Oligodendrocyte Fate after Spinal Cord Injury

2011

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Summary: Oligodendrocytes (OLs) are particularly susceptible to the toxicity of the acute lesion environment after spinal cord injury (SCI). They undergo both necrosis and apoptosis acutely, with apoptosis continuing at chronic time points. Loss of OLs causes demyelination and impairs axon function and survival. In parallel, a rapid and protracted OL progenitor cell proliferative response occurs, especially at the lesion borders. Proliferating and migrating OL progenitor cells differentiate into myelinating OLs, which remyelinate demyelinated axons starting at 2 weeks postinjury. The progression of OL lineage cells into mature OLs in the adult after injury recapitulates development to some degree, owing to the plethora of factors within the injury milieu. Although robust, this endogenous oligogenic response is insufficient against OL loss and demyelination. First, in this review we analyze the major spatial-temporal mechanisms of OL loss, replacement, and myelination, with the purpose of highlighting potential areas of intervention after SCI. We then discuss studies on OL protection and replacement. Growth factors have been used both to boost the endogenous progenitor response, and in conjunction with progenitor transplantation to facilitate survival and OL fate. Considerable progress has been made with embryonic stem cellderived cells and adult neural progenitor cells. For therapies targeting oligogenesis to be successful, endogenous responses and the effects of the acute and chronic lesion environment on OL lineage cells must be understood in detail, and in relation, the optimal therapeutic window for such strategies must also be determined.

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Interleukin‐1β promotes oligodendrocyte death through glutamate excitotoxicity

Cited by 233 publications

References 45 publications

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders

Tumor necrosis factor promoter haplotype associated with schizophrenia reveals a linked locus on 1q44

Oligodendrocyte Fate after Spinal Cord Injury

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