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The impact of metallothionein-II on microglial response to tumor necrosis factor-alpha (TNFα) and downstream effects on neuronal regeneration

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Leung, JYK ORCID: 0000-0001-8798-3932, Bennett, WR ORCID: 0000-0002-1559-3027, King, AE ORCID: 0000-0003-1792-0965 and Chung, RS 2018 , 'The impact of metallothionein-II on microglial response to tumor necrosis factor-alpha (TNFα) and downstream effects on neuronal regeneration' , Journal of neuroinflammation, vol. 15, no. 1 , pp. 1-9 , doi: 10.1186/s12974-018-1070-3.

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Abstract

Background: The extracellular environment plays an important role in supporting the regeneration of axons afterinjury. Metallothionein-II (MTII) is a metal-binding protein known for its neuroprotective effect by directly stimulatingthe growth of axons after injury. Previous studies have shown that MTII also modulates the response of astrocytes andmicroglia after injury. However, a detailed analysis describing how MTII modulates the interaction between microgliaand neurons is lacking.Methods: We introduced fluorescently labelled MTII into the cortex at the time of needlestick injury to investigate thecellular uptake of MTII using immunohistochemistry with antibodies against cell-type-specific markers. The role of MTIIin modulating the effect of microglia on axon outgrowth following an inflammatory response is further investigatedusing a co-culture model involving primary rodent microglia pre-treated with TNFα and primary rodent cortical neurons.The axon lengths were assessed 24 h after the plating of the neurons onto treated microglia. We also utilised siRNA toknockdown the expression of LRP1, which allows us to investigate the role of LRP1 receptors in the MTII-mediated effectof microglia on axon outgrowth.Results: Fluorescently labelled MTII was found to be associated with neurons, astrocytes and microglia following injuryin vivo. Microglia-neuron co-culture experiments demonstrated that exogenous MTII altered the response of microgliato TNFα. The neurons plated onto the TNFα-stimulated microglia pre-treated with MTII have shown a significantly longeraxonal length compare to the TNFα-stimulated microglia without the MTII treatment. This suggested that MTII reducecytokine-stimulated activation of microglia, which would ordinarily impair neurite outgrowth. This inhibitory effect of MTIIon activated microglia was blocked by siRNA-mediated downregulation of LRP1 receptor expression in microglia, suggestingthat MTII acts via the LRP1 receptor on microglia.Conclusions: This study demonstrates that exogenous MTII acts via the LRP1 receptor to alter the inflammatory response ofmicroglia following TNFα stimulation, providing a more supportive environment for axon growth.

Item Type: Article
Authors/Creators:Leung, JYK and Bennett, WR and King, AE and Chung, RS
Keywords: Metallothionein, traumatic brain injury, microglia
Journal or Publication Title: Journal of neuroinflammation
Publisher: BioMed Central
ISSN: 1742-2094
DOI / ID Number: 10.1186/s12974-018-1070-3
Copyright Information:

© 2018 The Authors. Licensed under Creative Commons Attribution 4.0 International (CC BY 4.0) https://creativecommons.org/licenses/by/4.0/

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