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Cited by 330Neuroinflammation and Neurodegeneration MechanismsMicroRNA in disease regulationInflammasome and immune disorders

MicroRNA-146a: A Key Regulator of Astrocyte-Mediated Inflammatory Response

Open access
Iyer, Anand, Zurolo, Emanuele, Prabowo, Avanita, Fluiter, Kees, Spliet, Wim G. M., van Rijen, Peter C., Gorter, Jan A., Aronica, Eleonora·2012·PLoS ONE
DOI 10.1371/journal.pone.0044789PMC PMC3441440
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Abstract

Increasing evidence supports the involvement of microRNAs (miRNA) in the regulation of inflammation in human neurological disorders. In the present study we investigated the role of miR-146a, a key regulator of the innate immune response, in the modulation of astrocyte-mediated inflammation. Using Taqman PCR and in situ hybridization, we studied the expression of miR-146a in epilepsy-associated glioneuronal lesions which are characterized by prominent activation of the innate immune response. In addition, cultured human astrocytes were used to study the regulation of miR-146a expression in response to proinflammatory cytokines. qPCR and western blot were used to evaluate the effects of overexpression or knockdown of miR-146a on IL-1β signaling. Downstream signaling in the IL-1β pathway, as well as the expression of IL-6 and COX-2 were evaluated by western blot and ELISA. Release several cytokines was evaluated using a human magnetic multiplex cytokine assay on a Luminex® 100™/200™ platform. Increased expression of miR-146a was observed in glioneuronal lesions by Taqman PCR. MiR-146a expression in human glial cell cultures was strongly induced by IL-1β and blocked by IL-1β receptor antagonist. Modulation of miR-146a expression by transfection of astrocytes with anti-miR146a or mimic, regulated the mRNA expression levels of downstream targets of miR-146a (IRAK-1, IRAK-2 and TRAF-6) and the expression of IRAK-1 protein. In addition, the expression of IL-6 and COX-2 upon IL-1β stimulation was suppressed by increased levels of miR-146a and increased by the reduction of miR-146a. Modulation of miR-146a expression affected also the release of several cytokines such as IL-6 and TNF-α. Our observations indicate that in response to inflammatory cues, miR-146a was induced as a negative-feedback regulator of the astrocyte-mediated inflammatory response. This supports an important role of miR-146a in human neurological disorders associated with chronic inflammation and suggests that this miR may represent a novel target for therapeutic strategies.

AI snapshot

Written from the paper’s full text.

TL;DR

This study shows that miR-146a is upregulated in epilepsy-associated glioneuronal lesions and is induced in cultured human glial cells by IL-1β, where it acts as a negative-feedback regulator of astrocyte-mediated inflammatory signaling. Modulating miR-146a alters downstream TIR-pathway targets and IL-1β-induced inflammatory mediators.

Key findings

  • miR-146a expression was significantly increased in ganglioglioma (GG) and focal cortical dysplasia type IIb (FCD IIb) compared with control cortex by qPCR (control cortex n=6 autopsy; FCD IIb n=6; GG n=5; *P<0.05). In situ hybridization showed miR-146a was undetectable in glial cells in control grey and white matter, but was expressed in GFAP-positive reactive astrocytes and balloon cells in FCD IIb; no detectable expression was seen in HLA-DR-positive microglial/macrophage cells.
  • In U373 glioblastoma cells and human fetal astrocytes, IL-1β strongly induced miR-146a; this was blocked by IL-1 receptor antagonist. LPS induced lower miR-146a and was blocked by LPS-RS, whereas IL-6 (10 ng/ml), TNFα (1 ng/ml), and HMGB1 (40 nM) did not significantly increase miR-146a. IL-1β effects began at 0.1 ng/ml, were maximal at 1–50 ng/ml, and increased miR-146a levels were detected 16 h after exposure.
  • Transfection with miR-146a mimic reduced IL-1β-stimulated IRAK-1, IRAK-2, and TRAF-6 mRNA and IRAK-1 protein; LNA-anti-miR-146a increased IRAK-1, IRAK-2, and TRAF-6 mRNA. No significant differences in IRAK-2 and TRAF-6 proteins were observed.
  • miR-146a mimic reduced IL-1β-induced IL-6 and COX-2 mRNA and COX-2 protein, while LNA-anti-miR-146a increased them. IL-1β increased release of IL-6, IL-8, IFN-γ, IP-10, MIP-1β, G-CSF, Rantes, and TNF-α; anti-miR-146a significantly increased IL-6 and IP-10, whereas mimic significantly decreased IL-6, IL-8, G-CSF, IFN-γ, IP-10, MIP-1β, and TNF-α. MCP-1 release was reduced by miR-146a mimic (control: 1582±193 pg/ml; IL-1β: 27151±1368 pg/ml; IL-1β + miR-146a mimic: 11054±2027 pg/ml; p<0.05 vs IL-1β).

Methods

  • Human surgical epilepsy specimens included GG and FCD IIb, with autopsy control cortex and histologically normal surgical temporal neocortex as controls. miR-146a expression was assessed by Taqman qPCR and in situ hybridization, including double labeling with GFAP or HLA-DR.
  • Cultured human glial cells included the U373 glioblastoma cell line and human fetal astrocyte-enriched cultures. Cells were treated with IL-1β, LPS, IL-6, TNFα, HMGB1, IL-1Ra, or LPS-RS, and transfected with LNA-anti-miR-146a or miR-146a mimic.
  • Downstream effects were measured by qPCR, western blot, ELISA for MCP-1, and a human magnetic multiplex cytokine assay on a Luminex 100/200 platform for 16 cytokines/chemokines. Statistics used two-tailed Student’s t-test or Kruskal–Wallis with Dunn’s post hoc test; P<0.05 was significant.

Limitations

  • Stated: further investigation is needed to evaluate levels of different miR-146a targets in GG and FCD, and balloon cell function could be evaluated in a culture system. The paper also notes that miR-146a effects on multiple targets may vary by cell type and stimulus, that IL-1β-induced miR-146a levels were not sufficient to significantly reduce the studied targets, and that overexpression was required to exert an anti-inflammatory effect.
  • Evident: human tissue sample sizes were small (control cortex n=6, FCD IIb n=6, GG n=5), and much of the mechanistic work used the U373 glioblastoma cell line and fetal astrocytes rather than adult human astrocytes in situ. Some fetal astrocyte results for IRAK-2 and TRAF-6 are described as “data not shown.”

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1371/journal.pone.0044789

Cites

57 of 57 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 44 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The LPS-induced increase in miR-146a was blocked by LPS-RS.

    “and blocked by LPS-RS (Fig. 2 A).”
    Quote in the paperSubstantial claim
  • Findingown data

    miR-146a mimic reduced COX-2 protein expression in IL-1β stimulated cells.

    “Western blot analysis confirmed the different effects of LNA-anti-miR-146a and miR-146a mimic on COX-2 protein expression in IL-1ß stimulated cells; transfection with miR-146a mimic reduced whereas LNA-anti-miR-146a increased the COX-2 expression (Fig. 7 A–B).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.
  • Findingown data

    In FCD specimens, miR-146a expression was detected in glial cells with typical astroglia morphology, particularly in areas of prominent gliosis.

    “In FCD specimens miR-146a expression was detected in glial cells with typical astroglia morphology, particularly in the areas of prominent gliosis (Fig. 1 D).”
    Quote in the paperSubstantial claim
  • Findingown data

    The IL-1β-induced increase in miR-146a expression is blocked by the IL-1β receptor antagonist (IL-1ra).

    “MiR-146a expression in human glial cell cultures was strongly induced by IL-1β and blocked by IL-1β receptor antagonist.”
    • Also stated in: § Regulation of miR-146a Expression by IL-1β in Human Glial Cells in Culture · plain
      “The effect of IL-1ß was blocked by the IL-1ß ra, a naturally occurring antagonist of the IL-1 receptor ([36]; Fig. 2 A and Fig. 3 A).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [36] Dinarello CA (1996) Biologic basis for interleukin-1 in disease. Blood 87: 2095– 2147. 8630372 source
  • Findingown data

    miR-146a expression in reactive astrocytes was observed in tissue specimens from patients with viral encephalitis.

    “miR-146a expression in reactive astrocytes was also observed in tissue specimens from patients with viral encephalitis and in tumor astrocytes in GG specimens (not shown).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 15
  • Classified as probably not a substantial claim. 8

  • May combine two claims.

    Findingown data

    Transfection with LNA-anti miR-146a increased mRNA levels of IRAK-1, IRAK-2 and TRAF-6 in U373 cells, and increased IRAK-1 mRNA in fetal astrocytes.

    “Increased mRNA levels of IRAK-1, IRAK-2 and TRAF-6 were observed after transfection with LNA-anti miR-146a (Fig. 5 B–C, U373; Fig. 5 D, IRAK-1, fetal astrocytes).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

  • May combine two claims.

    Findingown data

    LPS induced miR-146a expression, although to a lower extent compared to IL-1β.

    “Induction of miR-146a (although to a lower extent compared to IL-1ß) was also observed with LPS”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In vitro overexpression and knock-down studies showed that transfection with miR-146a mimic reduces IL-6 and COX-2 mRNA levels in cultures stimulated with IL-1β, whereas LNA-anti-miR-146a had the opposite effect.

    “The in vitro overexpression and knock-down studies showed that transfection with miR-146a mimic reduces the IL-6 and COX-2 mRNA levels in cultures stimulated with IL-1β, whereas LNA-anti-miR-146a had the opposite effect.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

  • May combine two claims.

    Findingown data

    The effect of IL-1β on miR-146a was concentration and time dependent and was observed from 16 hours after exposure to the cytokine.

    “The effect of IL-1β was concentration and time dependent and was observed from 16 hours after exposure to the cytokine.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

  • May combine two claims.

    Findingown data

    Both the U373 glioblastoma cell line and primary human fetal astrocytes exhibited prominent upregulation of miR-146a expression in response to IL-1β stimulation.

    “Both cell line and primary astrocytes were found to exhibit a prominent upregulation of miR-146a expression in response to IL-1β stimulation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

  • May combine two claims.

    Findingown data

    Transfection with LNA in the presence of IL-1β, which blocked the effect of miR-146a, further increased IRAK-1 and IRAK-2 mRNA, as well as IL-6 and COX-2 mRNA and protein levels in vitro.

    “Accordingly, transfection with LNA in the presence of IL-1ß which blocked the effect of miR-146a, further increased IRAK-1 and IRAK-2 mRNA, as well as IL-6 and COX-2 mRNA and protein levels in vitro.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

  • May combine two claims.

    Findingown data

    LPS induced modest up-regulation of miR-146a, whereas IL-6, TNFα and HMGB1 were not effective in inducing significant changes in miR-146a expression.

    “In contrast, LPS induced modest up-regulation whereas IL-6, TNFα and HMGB1 were not effective in inducing significant changes in miR-146a expression.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Sections without probe or with scramble probes were blank.

    “Sections without probe or with scramble probes were blank.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Upregulation of miR-146a has been detected in active multiple sclerosis lesions and in human Alzheimer disease brain.

    “In particular, upregulation of miR146a has been detected in active multiple sclerosis lesions [39] and in human Alzheimer disease (AD) brain [19], suggesting a key role of this miRNA in governing astrocyte activation and function in both pathologies.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [39] Junker A, Krumbholz M, Eisele S, Mohan H, Augstein F, et al (2009) MicroRNA profiling of multiple sclerosis lesions identifies modulators of the regulatory protein CD47. Brain 132: 3342– 3352. 19952055 source
    • cites [19] Cui JG, Li YY, Zhao Y, Bhattacharjee S, Lukiw WJ (2010) Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease. J Biol Chem 285: 38951– 38960. 20937840 PMC2998119 source

  • May combine two claims.

    Premisecitation

    miR-146a has been shown to be upregulated in experimental models of epilepsy and in human temporal lobe epilepsy.

    “The miR-146a has recently been shown to be upregulated in experimental models of epilepsy, as well as in human TLE. [20], [21].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [20] Aronica E, Fluiter K, Iyer A, Zurolo E, Vreijling J, et al (2010) Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci 31: 1100– 1107. 20214679

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [21] Song YJ, Tian XB, Zhang S, Zhang YX, Li X, et al.. (2011) Temporal Lobe epilepsy induces differential expression of hippocampal miRNAs including let-7e and miR-23a/b. Brain Res. 21376023 source

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Activation of microglia/macrophage lineage cells and astrocytes, and induction of inflammatory pathways, have been observed in focal malformations of cortical development such as focal cortical dysplasia.

    “Activation of cells of the microglia/macrophage lineage and astrocytes, and concomitant induction of various inflammatory pathways, also have been observed in focal malformations of cortical development (MCD; such as focal cortical dysplasia FCD), which represent major causes of pediatric epilepsy [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Blümcke I, Vinters HV, Armstrong D, Aronica E, Thom M, et al (2009) Malformations of Cortical Development and Epilepsies: Neuropathological findings with emphasis on Focal Cortical Dysplasia Epileptic. Disorders11: 181– 193. 19736171 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Various miRNAs are considered to represent a new class of mediators of inflammation.

    “Various miRNAs are also considered to represent a new class of mediators of inflammation [13]–[16].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [13] Sonkoly E, Stahle M, Pivarcsi A (2008) MicroRNAs and immunity: novel players in the regulation of normal immune function and inflammation. Seminars in Cancer Biology 18: 131– 140. 18291670 source
    • cites [14] Gantier MP (2010) New perspectives in MicroRNA regulation of innate immunity. J Interferon Cytokine Res 30: 283– 289. 20477549 source
    • cites [15] Quinn SR, O'Neill LA (2011) A trio of microRNAs that control Toll-like receptor signalling. Int Immunol 23: 421– 425. 21652514 source
    • cites [16] Rusca N, Monticelli S (2011) MiR-146a in Immunity and Disease. Mol Biol Int 2011: 437301. 22091404 PMC3200075 source

  • May combine two claims.

    Premisecitation

    miRNA-146a is upregulated in experimental models of epilepsy and in human temporal lobe epilepsy.

    “Interestingly, this miRNA has been shown to be upregulated in experimental models of epilepsy, as well as in human TLE [20]–[22].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [20] Aronica E, Fluiter K, Iyer A, Zurolo E, Vreijling J, et al (2010) Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci 31: 1100– 1107. 20214679

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

    • cites [21] Song YJ, Tian XB, Zhang S, Zhang YX, Li X, et al.. (2011) Temporal Lobe epilepsy induces differential expression of hippocampal miRNAs including let-7e and miR-23a/b. Brain Res. 21376023 source
    • cites [22] Omran A, Peng J, Zhang C, Xiang Q, Xue F, et al (2012) Interleukin-1b and microRNA-146a in an immature rat model and children with mesial temporal lobe epilepsy Epilepsia. 53: 1215– 1224. 22708826 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Gangliogliomas and focal cortical dysplasia type IIb represent a major cause of drug-resistant epilepsy.

    “GG and FCD type IIb represent a major cause of drug-resistant epilepsy [23], [25] and are characterized by a prominent activation of various inflammatory pathways, including the TIR signaling pathway [9], [40]–[43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [23] Blumcke I, Spreafico R (2011) An international consensus classification for focal cortical dysplasias. Lancet neurology 10: 26– 27. 21094091 source
    • cites [25] Thom M, Blumcke I, Aronica E (2012) Long-term epilepsy associated tumours. Brain Pathology doi:10.1111/j.1750–3639.2012.00582.x. PMC8029234 22497610 source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Transfection efficiency was around 80% by flow cytometry in both U373 and primary astrocytes.

    “Transfection efficiency was found to be around 80% by flow cytometry in both U373 and primary astrocytes.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductreasoning

    Histologically normal temporal neocortex from surgical patients was used to control for possible effects of recurrent seizures, antiepileptic drugs, or post mortem interval on miR-146a expression.

    “Furthermore, we also used histologically normal temporal neocortex from patients undergoing extensive surgical resection of the mesial structures for the treatment of medically intractable complex partial epilepsy to control for a possible effect of recurrent seizures, antiepileptic drugs or post mortem interval on the expression of miR146a.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    miRNAs play a critical role in post-transcriptional gene regulation in several biological processes of the central nervous system and in the pathogenesis of different disorders.

    “An increasing body of literature supports the critical role of miRNAs in post-transcriptional gene regulation in several biological processes of the central nervous system (CNS), as well as in the pathogenesis of different disorders (including developmental, neurodegenerative, vascular and neuroinflammatory disorders), and in oncogenesis [10]–[12].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Sethi P, Lukiw WJ (2009) Micro-RNA abundance and stability in human brain: specific alterations in Alzheimer's disease temporal lobe neocortex. Neurosci Lett 459: 100– 104. 19406203 source
    • cites [11] Li L, Chen XP, Li YJ (2010) MicroRNA-146a and human disease. Scandinavian J Immunol 71: 227– 231. 20384865 source
    • cites [12] Urbich C, Kuehbacher A, Dimmeler S (2008) Role of microRNAs in vascular diseases, inflammation, and angiogenesis. Cardiovasc Res 79: 581– 588. 18550634 source

  • May combine two claims.

    Premisecitation

    In a rat model of temporal lobe epilepsy, strong upregulation of miR-146a was detected in astrocytes 1 week after status epilepticus during epileptogenesis, corresponding to the latent period and time of maximal astroglial activation and upregulation of immune response genes.

    “In a rat model of TLE strong upregulation was detected in astrocytes 1 week after status epilepticus (during epileptogenesis) which corresponds to the latent period and the time of maximal astroglial activation and upregulation of various genes involved in the immune response [37], [38].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Gorter JA, Van Vliet E, Aronica E, Rauwerda H, Breit T, et al (2006) Potential New Antiepileptogenic Targets Indicated by Microarray Analysis in a Rat Model for Temporal Lobe Epilepsy. Journal of Neuroscience 26: 11083– 11110. 17065450 PMC6674659 source
    • cites [38] Aronica E, Gorter J (2007) Gene Expression Profile in Temporal Lobe Epilepsy. Neuroscientist 13: 1– 9. 17404370

      Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductcitation

    All cases were reviewed independently by two neuropathologists and the diagnosis was confirmed according to the international consensus classification system for grading FCD.

    “All cases were reviewed independently by two neuropathologists and the diagnosis was confirmed according to the international consensus classification system recently proposed for grading FCD [23].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Blumcke I, Spreafico R (2011) An international consensus classification for focal cortical dysplasias. Lancet neurology 10: 26– 27. 21094091 source

  • May combine two claims.

    Interpretationreasoning

    Although IL-1β increased miR-146a levels, these levels were not sufficient to significantly reduce the expression of the miR-146a targets studied.

    “Although IL-1ß increased miR-146a levels, these levels were not sufficient to significantly reduce the expression of the miR-146a targets studied.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.
20 of 20

  • The paper relies on this without support.

    The regulation of miR-146a in cultured human fetal astrocytes and U373 cells by IL-1β reflects the regulation of miR-146a in astrocytes in human epilepsy-associated lesions in vivo.

    “Furthermore, we investigated the regulation of miR-146a in response to inflammatory molecules in cultured human glial cells (U373 glioblastoma cell line and human astrocytes cell cultures) and further evaluated its role in regulating TLR/IL-1R-interleukin-1 receptor-associated kinase (IRAK)-NF-κB signaling, particularly in astroglia.”

  • The paper relies on this without support.

    There is little information regarding miR-146a function in astrocytes, particularly its effect on astroglia-mediated inflammatory pathways in relation to epilepsy.

    “However, there is still little information regarding miR-146a function in astrocytes, in particular regarding the effect on astroglia mediated inflammatory pathways in relation to epilepsy.”

  • The paper relies on this without support.

    The U373 glioblastoma cell line and human fetal astrocytes in culture are adequate models of human glial cells in epileptogenic lesions for studying miR-146a-mediated inflammatory responses.

    “Since miR-146a was up-regulated in astrocytes in the epileptogenic lesions (FCD, present results; TLE [20], [21]) the expression of miR-146a was further analyzed in culture, using U373 glioblastoma cell line and human fetal astrocytes.”
3 of 3

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Anti-miR-146a concentration differs between methods and Figure 5

    Minor

    The transfection protocol specifies a final anti-miR-146a LNA concentration of 50 nM, whereas Figure 5 specifies 25 nM for the U373 experiments.

  • IL-1β effect on IRAK-1 protein is described inconsistently

    Minor

    The results say IL-1β induced downregulation of IRAK-1 protein, a studied miR-146a target. The discussion instead says IL-1β-induced miR-146a was insufficient to significantly reduce expression of the targets studied.

  • Surgical specimen total conflicts with Figure 1 sample sizes

    Minor

    The methods state that six surgical brain specimens were examined, but Figure 1 reports six FCD and five GG surgical specimens, totaling eleven.

3 of 3

Cites

Flagged first, then by citations

1 of the 58 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. [43]Iyer A, Zurolo E, Spliet WG, van Rijen PC, Baayen JC, et al (2010) Evaluation of the innate and adaptive immunity in type I and type II focal cortical dysplasias. Epilepsia 51: 1763– 1773. 20345941

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Authors
Iyer, A., Zurolo, E., Prabowo, A., Fluiter, K., Spliet, W. G. M., van Rijen, P. C., Gorter, J. A., & Aronica, E.
Affiliations
  • Amsterdam UMC Location University of Amsterdam (NL)
  • University Medical Center Utrecht (NL)
  • Stichting Epilepsie Instellingen Nederland (NL)
Corresponding author
Aronica, Eleonora
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2012-09-13
Volume
7
Issue
9
Pages
e44789
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0044789
PMC
PMC3441440
OpenAlex
W2138125988
Cited by
330
References
58
Citations by year
2026: 15 · 2025: 17 · 2024: 12 · 2023: 11 · 2022: 17 · 2021: 18 · 2020: 21 · 2019: 25 · 2018: 30 · 2017: 36 · 2016: 41 · 2015: 29 · 2014: 28 · 2013: 29 · 2012: 1
FWCI
13.20
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • UvA-DARE (University of Amsterdam) (publishedVersion, cc-by)
  • Pure Amsterdam UMC (publishedVersion)
  • Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
  • Data Archiving and Networked Services (DANS) (submittedVersion)
  • UvA-DARE (University of Amsterdam) (submittedVersion, cc-by)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Utrecht University Repository (Utrecht University) (submittedVersion, other-oa)
  • Figshare (submittedVersion, cc-by)
Funders
  • European Commission (202167, 278486)
  • Stichting Kinderen Kankervrij
  • Hersenstichting (NEF 13-01)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
Keywords
microRNA-146a, astrocytes, innate immune response, epilepsy, IL-1β signaling, IRAK1, TRAF6, interleukin-6, cyclooxygenase-2, TNF-α, negative feedback regulation, anti-inflammatory therapy
MeSH terms
Astrocytes, Brain Diseases, Epilepsy, Female, Gene Expression Regulation, Humans, Immunity, Innate, Male, Pregnancy, Signal Transduction, Interleukin-6, NF-kappa B, Receptors, Interleukin-1, Ganglioglioma, Inflammation Mediators, MicroRNAs, Cell Line, Tumor, TNF Receptor-Associated Factor 6, Toll-Like Receptors, Cyclooxygenase 2, Interleukin-1beta, Interleukin-1 Receptor-Associated Kinases, Malformations of Cortical Development, Malformations of Cortical Development, Group I

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