Tumor Necrosis Factor Inhibits Neurite Outgrowth and Branching of Hippocampal Neurons by a Rho-Dependent Mechanism

Neumann, Harald; Schweigreiter, Rüdiger; Yamashita, Toshio; Rosenkranz, Katja; Wekerle, Hartmut; Barde, Yves‐Alain

doi:10.1523/jneurosci.22-03-00854.2002

Cited by 290 publications

(216 citation statements)

References 54 publications

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“…At the higher dose (1000 U), IL-1b, IL-6, and TNFa caused a significant reduction in each parameter of dendrite morphology. These findings are consistent with a recent study reporting that TNFa significantly decreased neurite outgrowth and branching of hippocampal neurons in culture (Neumann et al, 2002). Interferon-g also inhibits dendritic growth in hippocampal neurons (Kim et al, 2002).…”

Section: Discussionsupporting

confidence: 93%

“…IL-6 and TNFa can decrease b-catenin expression in hepatocarcinoma cells (Cervello et al, 2001) and in bronchial epithelial cells (Carayol et al, 2002), suggesting that cytokines may act through a mechanism that involves b-catenin in developing dendrites. As noted above, TNFa significantly decreased dendrite development of hippocampal neurons; this effect involved a Rho GTPasedependent mechanism that also regulates the cytoskeleton (Neumann et al, 2002). These studies suggest that regulation of the cytoskeleton is a potential mechanism through which cytokines can inhibit the development of dendrites.…”

Section: Discussionsupporting

confidence: 57%

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Prenatal Infection and Risk for Schizophrenia: IL-1β, IL-6, and TNFα Inhibit Cortical Neuron Dendrite Development

Gilmore¹,

Jarskog²,

Vadlamudi³

et al. 2004

Neuropsychopharmacol

236

158

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Prenatal exposure to infection increases risk for schizophrenia, and we have hypothesized that inflammatory cytokines, generated in response to maternal infection, alter neuron development and increase risk for schizophrenia. We sought to study the effect of cytokines generated in response to infectionFinterleukin-1b (IL-1b), tumor necrosis factor-a (TNFa), and interleukin-6 (IL-6)Fon the dendritic development of cortical neurons. Primary mixed neuronal cultures were obtained from E18 rats and exposed to 0, 100, or 1000 units (U)/ml of IL-1b, TNFa, IL-6, or IL-1b þ TNFa for 44 h. MAP-2-positive neurons were randomly identified for each condition and the number of primary dendrites, nodes, and total dendrite length was determined. We found that 100 U of TNFa significantly reduced the number of nodes (27%, p ¼ 0.02) and total dendritic length (14%, p ¼ 0.04), but did not affect overall neuron survival. A measure of 100 U IL-1b þ TNFa significantly reduced the number of primary dendrites (17%, p ¼ 0.006), nodes (32%, p ¼ 0.001), and total dendritic length (30%, po0.0001), although it did not affect overall neuron survival. At 1000 U, each cytokine significantly reduced the number of primary dendrites (14-24%), nodes (28-37%), as well as total dendritic length (25-30%); neuron survival was reduced by 14-21%. These results indicate that inflammatory cytokines can significantly reduce dendrite development and complexity of developing cortical neurons, consistent with the neuropathology of schizophrenia. These findings also support the hypothesis that cytokines play a key mechanistic role in the link between prenatal exposure to infection and risk for schizophrenia.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 57%

Prenatal Infection and Risk for Schizophrenia: IL-1β, IL-6, and TNFα Inhibit Cortical Neuron Dendrite Development

Gilmore¹,

Jarskog²,

Vadlamudi³

et al. 2004

Neuropsychopharmacol

236

158

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“…Interestingly, our data provide a counterpoint to the effect of TNF␣ or trauma on the activation state of Rho GTPases in neurons (Neumann et al, 2002;Dubreuil et al, 2003). Our results suggest that the initiating signal of a reactive astrogliosis is associated not with activation of Rho GTPases, but, conversely, with their deactivation.…”

Section: Discussionmentioning

confidence: 60%

“…The Rho-ROCK-MLC axis thus appears to be the critical controller of these processes in mammalian systems, in turn suggesting the potential for the involvement of this pathway in the effects of IL-1␤ on astrocyte structure. Interactions between cytokine signaling and small GTPases, including Rho, have been reported in fibroblasts, HeLa cells, and neurons (Puls et al, 1999;Singh et al, 1999, Neumann et al, 2002, but such interactions have not previously been implicated in the generation of a reactive astrogliosis.…”

Section: Discussionmentioning

confidence: 99%

Interleukin-1β Induces a Reactive Astroglial Phenotype via Deactivation of the Rho GTPase–Rock Axis

John

Chen²,

Rivieccio³

et al. 2004

J. Neurosci.

152

126

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The cytokine interleukin-1␤ (IL-1␤) is critical to the formation of an astrocytic scar after CNS injury, but the mechanisms by which it induces a reactive phenotype remain unresolved. Here, we show that IL-1␤ regulates the phenotype of astrocytes via deactivation of the Rho GTPase-Rho kinase (ROCK) pathway, which governs cellular morphology and migration via effects on F-actin and its interactions with focal adhesions, nonmuscle myosin, and microvillar adapter proteins of the ezrin-radixin-moesin (ERM) family. We found that IL-1␤ induced cortical reorganization of F-actin and dephosphorylation of focal adhesion kinase, myosin light chain 2, and myosin phosphatase targeting subunit 1 in primary human astrocytes, and that all of these effects were mimicked by Rho-ROCK pathway blockade. We also found that IL-1␤ conversely potentiated ERM phosphorylation, and that this effect was mediated via a Rho-ROCKindependent mechanism. Next, we used a rhotekin pulldown assay to confirm directly that IL-1␤ deactivates Rho, and further demonstrated that a constitutively active Rho construct rescued astrocytes from developing an IL-1␤-induced reactive phenotype. These data implicate cytokine regulation of the Rho-ROCK pathway in the generation of a reactive astrogliosis, and we suggest that interventions targeted at this level may facilitate manipulation of the glial scar in inflammatory disorders of the human CNS.

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“…Previous studies have demonstrated that TNF-α or glutamate can activate RhoA and Rho kinase [39][40][41]. RhoA is an essential component of the excitotoxicity pathway, and is sufficient to induce the activation of such pathway [42].…”

Section: Discussionmentioning

confidence: 99%

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

Walker

et al. 2016

Mol Neurobiol

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Activation of RhoA/Rho kinase leads to growth cone collapse and neurite retraction. Although RhoA/Rho kinase inhibition has been shown to improve axon regeneration, remyelination and functional recovery, its role in neuronal cell death remains unclear. To determine whether RhoA/Rho kinase played a role in neuronal death after injury, we investigated the relationship between RhoA/Rho kinase and cytosolic phospholipase A 2 (cPLA 2 ), a lipase that mediates inflammation and cell death, using an in vitro neuronal death model and an in vivo contusive spinal cord injury model performed at the 10 th thoracic (T10) vertebral level. We found that coadministration of TNF-α and glutamate induced spinal neuron death, and activation of RhoA, Rho kinase and cPLA 2 . Inhibition of RhoA, Rho kinase and cPLA 2 significantly reduced TNF-α/glutamate-induced cell death by 33%, 52% and 43%, respectively (p < 0.001). Inhibition of RhoA and Rho kinase also significantly down-regulated cPLA 2 activation by 66% and 60%, respectively (p < 0.01). Furthermore, inhibition of RhoA and Rho kinase reduced the release of arachidonic acid, a downstream substrate of cPLA 2 . The immunofluorescence staining showed that ROCK 1 or ROCK 2, two isoforms of Rho kinase, was co-localized with cPLA 2 in neuronal cytoplasm. Interestingly, co-immunoprecipitation (Co-IP) assay showed that ROCK 1 or ROCK 2 , bonded directly with cPLA 2 and phospho-cPLA 2 . When the Rho kinase inhibitor Y27632 was applied in mice with T10 contusion injury, it significantly decreased cPLA 2 activation and expression, and reduced injury-induced apoptosis in the lesion area. Taken together, our results reveal a novel mechanism of RhoA/Rho kinase-mediated neuronal death through regulating cPLA 2 activation.

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Tumor Necrosis Factor Inhibits Neurite Outgrowth and Branching of Hippocampal Neurons by a Rho-Dependent Mechanism

Cited by 290 publications

References 54 publications

Prenatal Infection and Risk for Schizophrenia: IL-1β, IL-6, and TNFα Inhibit Cortical Neuron Dendrite Development

Prenatal Infection and Risk for Schizophrenia: IL-1β, IL-6, and TNFα Inhibit Cortical Neuron Dendrite Development

Interleukin-1β Induces a Reactive Astroglial Phenotype via Deactivation of the Rho GTPase–Rock Axis

RhoA/Rho Kinase Mediates Neuronal Death Through Regulating cPLA2 Activation

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