Abstract：
BACKGROUND:Over-activated microglia play a central role during neuroinflammation, leading to neuronal cell death and neurodegeneration. Reversion of over-activated to neuroprotective microglia phenotype could regenerate a healthy CNS-supporting microglia environment. Our aim was to identify a dataset of intracellular molecules in primary microglia that play a role in the transition of microglia to a ramified, neuroprotective phenotype. METHODS:We exploited the anti-inflammatory and neuroprotective properties of conditioned medium of adipose-derived mesenchymal stem cells (CM) as a tool to generate the neuroprotective phenotype of microglia in vitro, and we set up a microscopy-based siRNA screen to identify its hits by cell morphology. RESULTS:We initially assayed an array of 157 siRNAs against genes that codify proteins and factors of cytoskeleton and activation/inflammatory pathways in microglia. From them, 45 siRNAs significantly inhibited the CM-induced transition from a neurotoxic to a neuroprotective phenotype of microglia, and 50 siRNAs had the opposite effect. As a proof-of-concept, ten of these targets were validated with individual siRNAs and by downregulation of protein expression. This validation step resulted essential, because three of the potential targets were false positives. The seven validated targets were assayed in a functional screen that revealed that the atypical RhoGTPase RhoE/Rnd3 is necessary for BDNF expression and plays an essential role in controlling microglial migration. CONCLUSIONS:Besides the identification of RhoE/Rnd3 as a novel inducer of a potential neuroprotective phenotype in microglia, we propose a list of potential targets to be further confirmed with selective activators or inhibitors.
journal_name
J Neuroinflammationjournal_title
Journal of neuroinflammationauthors
Neubrand VE,Forte-Lago I,Caro M,Delgado Mdoi
10.1186/s12974-018-1386-zsubject
Has Abstractpub_date
2018-12-15 00:00:00pages
343issue
1issn
1742-2094pii
10.1186/s12974-018-1386-zjournal_volume
15pub_type
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pub_type： 杂志文章,评审
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pub_type： 杂志文章,收录出版
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pub_type： 杂志文章
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更新日期：2018-09-24 00:00:00
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doi：10.1186/1742-2094-9-138
更新日期：2012-06-22 00:00:00
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pub_type： 杂志文章
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更新日期：2015-09-15 00:00:00
abstract：BACKGROUND:Recent evidence has suggested that peripheral inflammatory responses induced by lipopolysaccharides (LPS) play an important role in neuropsychiatric dysfunction in rodents. Interleukin-1β (IL-1β), a pro-inflammatory cytokine, has been proposed to be a key mediator in a variety of behavioral dysfunction induc...
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pub_type： 杂志文章
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更新日期：2017-09-20 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章
doi：10.1186/s12974-016-0613-8
更新日期：2016-06-10 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章,评审
doi：10.1186/s12974-019-1608-z
更新日期：2019-11-06 00:00:00
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pub_type： 杂志文章
doi：10.1186/1742-2094-10-131
更新日期：2013-10-29 00:00:00
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journal_title：Journal of neuroinflammation
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doi：10.1186/1742-2094-8-57
更新日期：2011-05-24 00:00:00
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pub_type： 杂志文章
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更新日期：2017-06-06 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章
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更新日期：2016-01-27 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章
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更新日期：2017-12-12 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章
doi：10.1186/1742-2094-11-4
更新日期：2014-01-08 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章
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pub_type： 杂志文章
doi：10.1186/s12974-019-1418-3
更新日期：2019-02-12 00:00:00
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journal_title：Journal of neuroinflammation
pub_type： 杂志文章
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更新日期：2015-01-15 00:00:00
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doi：10.1186/1742-2094-10-38
更新日期：2013-03-14 00:00:00
