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Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia.

Xia Q, Hu Q, Wang H, Yang H, Gao F, Ren H, Chen D, Fu C, Zheng L, Zhen X, Ying Z, Wang G - Cell Death Dis (2015)

Bottom Line: Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS.However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood.Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.

ABSTRACT
Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

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Neuronal death is mediated by the classical MAPK signaling pathway and upregulated PGE2 in TDP-43-depleted microglia. The schematic illustrates the mechanism by which TDP-43-depleted microglia, but not TDP-43-depleted astrocytes, induce neuronal death. The MAPK/ERK signaling pathway is activated in TDP-43-depleted microglia, resulting in increased COX-2 and PGE2, which then trigger neuronal death. Inhibition of COX-2 and PGE2 production using celecoxib alleviates neuronal death mediated by TDP-43-depleted microglia
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fig7: Neuronal death is mediated by the classical MAPK signaling pathway and upregulated PGE2 in TDP-43-depleted microglia. The schematic illustrates the mechanism by which TDP-43-depleted microglia, but not TDP-43-depleted astrocytes, induce neuronal death. The MAPK/ERK signaling pathway is activated in TDP-43-depleted microglia, resulting in increased COX-2 and PGE2, which then trigger neuronal death. Inhibition of COX-2 and PGE2 production using celecoxib alleviates neuronal death mediated by TDP-43-depleted microglia

Mentions: Although initially, most studies on ALS focused on the selective loss of motor neurons themselves, increasing efforts to understand the role of glial cells in disease pathogenesis have come to the forefront of the field. The present study reveals microglia-mediated COX-2-PGE2 production as the molecular determinant of TDP-43-associated neurotoxicity, emphasizing the important contribution of microglia to non-cell-autonomous motor neuron degeneration in TDP-43-linked ALS (Figure 7).


Induction of COX-2-PGE2 synthesis by activation of the MAPK/ERK pathway contributes to neuronal death triggered by TDP-43-depleted microglia.

Xia Q, Hu Q, Wang H, Yang H, Gao F, Ren H, Chen D, Fu C, Zheng L, Zhen X, Ying Z, Wang G - Cell Death Dis (2015)

Neuronal death is mediated by the classical MAPK signaling pathway and upregulated PGE2 in TDP-43-depleted microglia. The schematic illustrates the mechanism by which TDP-43-depleted microglia, but not TDP-43-depleted astrocytes, induce neuronal death. The MAPK/ERK signaling pathway is activated in TDP-43-depleted microglia, resulting in increased COX-2 and PGE2, which then trigger neuronal death. Inhibition of COX-2 and PGE2 production using celecoxib alleviates neuronal death mediated by TDP-43-depleted microglia
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4385945&req=5

fig7: Neuronal death is mediated by the classical MAPK signaling pathway and upregulated PGE2 in TDP-43-depleted microglia. The schematic illustrates the mechanism by which TDP-43-depleted microglia, but not TDP-43-depleted astrocytes, induce neuronal death. The MAPK/ERK signaling pathway is activated in TDP-43-depleted microglia, resulting in increased COX-2 and PGE2, which then trigger neuronal death. Inhibition of COX-2 and PGE2 production using celecoxib alleviates neuronal death mediated by TDP-43-depleted microglia
Mentions: Although initially, most studies on ALS focused on the selective loss of motor neurons themselves, increasing efforts to understand the role of glial cells in disease pathogenesis have come to the forefront of the field. The present study reveals microglia-mediated COX-2-PGE2 production as the molecular determinant of TDP-43-associated neurotoxicity, emphasizing the important contribution of microglia to non-cell-autonomous motor neuron degeneration in TDP-43-linked ALS (Figure 7).

Bottom Line: Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS.However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood.Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Molecular Neuropathology, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases and College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu, China.

ABSTRACT
Neuroinflammation is a striking hallmark of amyotrophic lateral sclerosis (ALS) and other neurodegenerative disorders. Previous studies have shown the contribution of glial cells such as astrocytes in TDP-43-linked ALS. However, the role of microglia in TDP-43-mediated motor neuron degeneration remains poorly understood. In this study, we show that depletion of TDP-43 in microglia, but not in astrocytes, strikingly upregulates cyclooxygenase-2 (COX-2) expression and prostaglandin E2 (PGE2) production through the activation of MAPK/ERK signaling and initiates neurotoxicity. Moreover, we find that administration of celecoxib, a specific COX-2 inhibitor, greatly diminishes the neurotoxicity triggered by TDP-43-depleted microglia. Taken together, our results reveal a previously unrecognized non-cell-autonomous mechanism in TDP-43-mediated neurodegeneration, identifying COX-2-PGE2 as the molecular events of microglia- but not astrocyte-initiated neurotoxicity and identifying celecoxib as a novel potential therapy for TDP-43-linked ALS and possibly other types of ALS.

Show MeSH
Related in: MedlinePlus