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Cited by 788Neuroinflammation and Neurodegeneration MechanismsMultiple Sclerosis Research StudiesMicroRNA in disease regulation

MicroRNA-124 promotes microglia quiescence and suppresses EAE by deactivating macrophages via the C/EBP-α–PU.1 pathway

Open access
Ponomarev, Eugene D, Veremeyko, Tatyana, Barteneva, Natasha, Krichevsky, Anna M, Weiner, Howard L·2011·Nature Medicine
DOI 10.1038/nm.2266PMC PMC3044940
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Abstract

MicroRNAs are a family of regulatory molecules involved in many physiological processes, including differentiation and activation of cells of the immune system. We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages. When overexpressed in macrophages, miR-124 directly inhibited the transcription factor CCAAT/enhancer-binding protein-α (C/EBP-α) and its downstream target PU.1, resulting in transformation of these cells from an activated phenotype into a quiescent CD45(low), major histocompatibility complex (MHC) class II(low) phenotype resembling resting microglia. During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia. Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages, reduced activation of myelin-specific T cells and marked suppression of disease. Conversely, knockdown of miR-124 in microglia and macrophages resulted in activation of these cells in vitro and in vivo. These findings identify miR-124 both as a key regulator of microglia quiescence in the central nervous system and as a previously unknown modulator of monocyte and macrophage activation.

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Crossref · 10.1038/nm.2266

Cites

45 of 45 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

1 of 26 cited sources checked · 1 supported · 0 flagged

  • Findingown data

    Most peripheral macrophages that infiltrate the CNS during EAE onset and at the peak of disease show an activated CD45hi MHC class II+ phenotype.

    “Most of the peripheral macrophages that infiltrated the CNS during EAE onset and at the peak of disease also showed an activated CD45hiMHC class II+ phenotype (Fig. 2a).”
    Quote in the paperNot a substantial claim
  • Findingown data

    In microglia, miR-124 expression decreases by approximately 70% during the course of EAE compared to healthy chimeras.

    “In microglia, miR-124 expression decreased by ~70% during the course of the disease, compared to healthy chimeras (Fig. 1d).”
    Quote in the paperSubstantial claim
  • Findingown data

    Peripheral administration of miR-124 in EAE causes systemic deactivation of macrophages.

    “Peripheral administration of miR-124 in EAE caused systemic deactivation of macrophages”
    • Also stated in: § miR-124 inhibits EAE and reduces CNS inflammation · plain
      “Subsequent experiments showed that peripheral administration of miR-124 during EAE directly affected macrophages and deactivated them”
    Quote in the paperSubstantial claim
  • Findingown data

    Conditional knockout of Cebpa ameliorates EAE.

    “Finally, we found that conditional knockout of the Cebpa gene also ameliorated EAE (Supplementary Data and Supplementary Fig. 9b).”
    Quote in the paperSubstantial claim
  • Findingown data

    During EAE, miR-124 is downregulated in activated microglia.

    “During experimental autoimmune encephalomyelitis (EAE), miR-124 was downregulated in activated microglia.”
    • Also stated in: § miR-124 is highly expressed by CNS-resident microglia · plain
      “In microglia, miR-124 expression decreased by ~70% during the course of the disease, compared to healthy chimeras (Fig. 1d).”
    Quote in the paperSubstantial claim
  • Classified as probably not a substantial claim. 8
  • May combine two claims. 35

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

    Premisecitation

    miR-124 is expressed in the CNS by neuronal cells.

    “miR-124 is known to be expressed in the CNS by neuronal cells23,39–41.”
    Quote in the paperNot a substantial claim1 of 4 sources checked
    • cites [23] Smirnova, L. et al. Regulation of miRNA expression during neural cell specification. Eur. J. Neurosci. 21, 1469–1477 (2005). source
    • cites [39] Mishima, T., Mizuguchi, Y., Kawahigashi, Y. & Takizawa, T. RT-PCR–based analysis of microRNA (miR-1 and -124) expression in mouse CNS. Brain Res. 1131, 37–43 (2007). source
    • cites [40] Visvanathan, J., Lee, S., Lee, B., Lee, J.W. & Lee, S.K. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 21, 744–749 (2007). source
    • cites [41] Kapsimali, M. et al. MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol. 8, R173 (2007). source

  • May combine two claims.

    Findingown data

    During EAE onset, approximately 40% of peripheral macrophages show a partially deactivated MHC class II− phenotype, whereas during recovery, approximately 40% become CD45low MHC class II−.

    “During onset of EAE, ~40% of peripheral macrophages showed a partially deactivated MHC class II− phenotype, whereas during recovery, ~40% of peripheral macrophages became CD45lowMHC class II− (Fig. 2a).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    During recovery, the level of MHC class II in microglia returns to normal, but a subset of cells remains CD45hi.

    “During recovery, the level of MHC class II in microglia returned to normal, but a subset of cells remained CD45hi, suggesting some residual level of activation.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In our experiments, activated microglia downregulated miR-124, and high levels of C/EBP-α expression were associated with the activated CD45hi phenotype.

    “In our experiments, activated microglia downregulated miR-124, and high levels of C/EBP-α expression were associated with the activated CD45hi phenotype.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment with miR-124 decreases the absolute numbers of lymphocytes, CD4 T cells, macrophages and activated CD45hi microglia in the CNS.

    “Figure 5d shows how the treatment with miR-124 decreased the absolute numbers of lymphocytes, CD4 T cells and macrophages and activated CD45hi microglia in the CNS.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mutations within two predicted miR-124 binding sites substantially reduce luciferase responsiveness to miR-124, and mutations within all three predicted sites nearly abolish it.

    “Mutations of this reporter construct within two predicted miR-124 binding sites (C/EBP-αmut1–2) substantially reduced the luciferase responsiveness to miR-124, and mutations within all three predicted sites (C/EBP-αmut1–3) nearly abolished it (Fig. 4e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Intravenously injected siRNA specific for C/EBP-α has similar effects on disease symptoms as miR-124, whereas mutant miR-124 lacking the C/EBP-α mRNA binding sequence has no effect on disease score.

    “Intravenously injected small interfering RNA (siRNA) specific for C/EBP-α had similar effects on disease symptoms, whereas mutant miR-124 lacking the C/EBP-α mRNA binding sequence had no effect on the disease score (Supplementary Data and Supplementary Fig. 9a).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Conditional knockout of Cebpa reduces C/EBP-α protein and results in reduced expression of PU.1, CD11b, MHC class II and CD86.

    “This conditional knockout reduced levels of C/EBP-α protein, which resulted in reduced expression of PU.1, CD11b, MHC class II and CD86 (Supplementary Data and Supplementary Fig. 7).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-124 is expressed in microglia but not in peripheral monocytes or macrophages.

    “We found that brain-specific miR-124 is expressed in microglia but not in peripheral monocytes or macrophages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Inflammatory lesions in the white matter of the lumbar spinal cord were evident in the control group but undetectable in miR-124-treated mice.

    “Inflammatory lesions containing nucleated and CD11b+ cells in the white matter of the lumbar spinal cord were evident in the control group but undetectable in the miR-124–treated mice (Fig. 5e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Intracranial injection of anti-miR-124 induces activation of CD11b+GFP+ microglia and alters their morphology.

    “When injected into C57BL/6→Cx3cr1GFP/+ chimeric mice that express GFP in microglia but not in peripheral macrophages, anti–miR-124 induced the activation of CD11b+GFP+ microglia and altered their morphology (Supplementary Data and Supplementary Fig. 16b–e).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-124 overexpression decreases the proportion of CD45hi C/EBP-α+ and CD45hi PU.1+ cells by 70% and 80%, respectively.

    “Quantification of the four experiments shows that miR-124 overexpression decreased the proportion of CD45hi C/EBP-α+ and CD45hiPU.1+ cells by 70% and 80%, respectively (Fig. 4d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Activated MHC class II+ peripheral macrophages express very low levels of miR-124, whereas deactivated MHC class II− macrophages upregulate miR-124 by 4.2-fold.

    “Activated MHC class II+ peripheral macrophages expressed very low levels of miR-124, whereas deactivated MHC class II− macrophages upregulated miR-124 by 4.2-fold (Fig. 2b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    During mouse prenatal and postnatal development, microglia show an activated phenotype with a low level of miR-124 expression.

    “During mouse prenatal and postnatal development, microglia showed an activated phenotype with a low level of miR-124 expression (Supplementary Data and Supplementary Fig. 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Transfection of macrophages with miR-124 inhibits expression of TNF-α and inducible nitric oxide synthase, and upregulates TGF-β1 and M2 markers arginase I and FIZZ1.

    “Transfection of macrophages with miR-124 also inhibited expression of TNF-α (Fig. 3c) and inducible nitric oxide synthase (Fig. 3d) by these cells, and upregulated both the anti-inflammatory cytokine TGF-β1 (Fig. 3d,e) and markers of alternatively activated (M2) macrophages arginase I and FIZZ1 (Fig. 3d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transfection with miR-124 reduces the number of proliferating cells and alters cell morphology.

    “Transfection with miR-124 also resulted in a reduced number of proliferating cells and altered cell morphology (Supplementary Data and Supplementary Fig. 4).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    miR-124 suppresses EAE in SJL mice and in Ifng−/− mice.

    “Disease symptoms were also substantially ameliorated in both EAE-prone SJL mice as well as in Ifng−/− mice, which have a more severe form of EAE (Supplementary Data and Supplementary Fig. 8a,b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Transfection of macrophages with miR-124 downregulates both CD45 and C/EBP-α, and the C/EBP-α− phenotype corresponds to the CD45low phenotype.

    “Two-color flow cytometry further confirmed that transfection of macrophages with miR-124 resulted in downregulation of both CD45 and C/EBP-α (Fig. 4c), and indicated that the C/EBP-α− phenotype corresponded to the CD45low phenotype of macrophages.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    miR-223 is expressed in peripheral macrophages but not in microglia.

    “whereas myeloid-specific miR-223 (refs. 6,22) was expressed in the macrophages in the periphery, but not in the microglia (Fig. 1b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [6] Johnnidis, J.B. et al. Regulation of progenitor cell proliferation and granulocyte function by microRNA-223. Nature 451, 1125–1129 (2008). source
    • cites [22] Fukao, T. et al. An evolutionarily conserved mechanism for microRNA-223 expression revealed by microRNA gene profiling. Cell 129, 617–631 (2007). source

  • May combine two claims.

    Findingown data

    In mice with EAE treated with miR-124, the CNS had primarily CD11b+CD45low resting microglia and no signs of microglia activation or leukocyte infiltration, whereas control mice had activated macrophages/microglia and leukocytes.

    “In contrast, the mice treated with miR-124 had primarily CD11b+CD45low resting microglia (Fig. 5c, miR-124, region R1) and no signs of microglia activation or leukocyte infiltration in the CNS (Fig. 5c, miR-124, regions R2 and R3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Treatment of mice with miR-124 at the onset of EAE substantially ameliorates clinical symptoms and enhances recovery.

    “Treatment of mice with miR-124 at the onset of EAE (starting day 13 after EAE induction) also substantially ameliorated clinical symptoms and enhanced recovery (Fig. 5b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Peripheral administration of miR-124 during EAE directly affects macrophages and deactivates them, and indirectly reduces activation of autoimmune CD4 T cells.

    “Subsequent experiments showed that peripheral administration of miR-124 during EAE directly affected macrophages and deactivated them, and indirectly reduced the activation of autoimmune CD4 T cells (Supplementary Data, Supplementary Figs. 10–15 and Supplementary Table 3).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    C/EBP-α expression is reduced in miR-124-transfected BMDMs by 50-70% at the protein level and by 50% at the mRNA level.

    “C/EBP-α expression was reduced in miR-124–transfected BMDMs by 50–70% on the protein level (Fig. 4b) and by 50% on the mRNA level (Fig. 3d).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    The highest level of miR-124 expression is in resting CD45low MHC class II− microglia, whereas activated MHC class II+ microglia express 60% lower miR-124.

    “The highest level of miR-124 expression was observed in resting CD45lowMHC class II− microglia, whereas activated MHC class II+ microglia expressed a 60% lower level of miR-124 (Fig. 2b).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    miR-124 not only deactivates macrophages but also skews their polarization from an M1 toward an M2 phenotype.

    “These data suggest that miR-124 not only deactivates macrophages but also skews their polarization from an M1 toward an M2 phenotype.”
    Quote in the paperSubstantial claim

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

    Study design and conductcitation

    The study acknowledges that CD11b+F4/80+ cells may include small numbers of myeloid dendritic cells and that peripheral macrophages may be contaminated by small numbers of GFP+ microglia.

    “In this study, we refer to cells expressing CD11b+F4/80+ as ‘macrophages’ even though they may include small numbers of CD11b+CD11c+F4/80+ myeloid dendritic cells. Peripheral macrophages may also be contaminated by small numbers of GFP+ microglia that enter the CNS during reconstitution14.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [14] Ponomarev, E.D., Shriver, L.P., Maresz, K. & Dittel, B.N. Microglial cell activation and proliferation precedes the onset of CNS autoimmunity. J. Neurosci. Res. 81, 374–389 (2005). source

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

    Premisecitation

    TNFR1 is a direct downstream target for C/EBP-α and C/EBP-β.

    “It has previously been shown that the TNF receptor (TNFR1) is a direct downstream target for C/EBP-α and C/EBP-β35”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Bristol, J.A., Morrison, T.E. & Kenney, S.C. CCAAT/enhancer binding proteins α and β regulate the tumor necrosis factor receptor 1 gene promoter. Mol. Immunol. 46, 2706–2713 (2009). source

  • May combine two claims.

    Interpretationown data

    In vivo administration of miR-124 directly affects macrophages, and this results in deficient activation of encephalitogenic T cells.

    “Our extensive analysis showed that in vivo administration of miR-124 directly affected macrophages, and this, in turn, resulted in deficient activation of encephalitogenic T cells (Supplementary Discussion).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    miR-124 controls multiple markers of macrophage activation by direct inhibition of C/EBP-α and its downstream transcription factor PU.1.

    “These data suggest that miR-124 controls multiple markers of macrophage activation by direct inhibition of C/EBP-α and its downstream transcription factor PU.1.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    miR-124 directly targets the mRNA encoding C/EBP-α and reduces expression of this protein.

    “These data confirm that miR-124 directly targets the mRNA encoding C/EBP-α and reduces expression of this protein.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    miR-124 inhibits proliferation and induces differentiation of medulloblastoma and glioblastoma cancer cells.

    “In addition, miR-124 inhibits proliferation and induces differentiation of medulloblastoma and glioblastoma cancer cells, which originate from immature neural cells43,44.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Pierson, J., Hostager, B., Fan, R. & Vibhakar, R. Regulation of cyclin dependent kinase 6 by microRNA 124 in medulloblastoma. J. Neurooncol. 90, 1–7 (2008). source
    • cites [44] Silber, J. et al. miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 6, 14 (2008). source

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

    Premisecitation

    TNF-α and TNFR1 may enhance each other's expression by an autocrine-paracrine mechanism.

    “and that TNF-α and TNFR1 may enhance each other's expression by an autocrine-paracrince mechanism36,37.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [36] Trefzer, U. et al. The 55-kD tumor necrosis factor receptor on human keratinocytes is regulated by tumor necrosis factor-α and by ultraviolet B radiation. J. Clin. Invest. 92, 462–470 (1993). source
    • cites [37] Cardinaux, J.R., Allaman, I. & Magistretti, P.J. Pro-inflammatory cytokines induce the transcription factors C/EBPβ and C/EBPδ in astrocytes. Glia 29, 91–97 (2000). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Treatment of mice with miR-124 ameliorates both EAE symptoms and inflammation in the CNS.

    “Thus, treatment of mice with miR-124 ameliorated both EAE symptoms and inflammation in the CNS.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    miR-124 promotes differentiation of neuronal progenitors to mature neurons by targeting small C-terminal domain phosphatase-1 and polypyrimidine tract-binding protein-1.

    “It promotes differentiation of neuronal progenitors to mature neurons by targeting small C-terminal domain phosphatase-1 and polypyrimidine tract–binding protein-1 that repress expression of neuronal genes in non-neuronal cells18,20,40.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [18] Cheng, L.C., Pastrana, E., Tavazoie, M. & Doetsch, F. miR-124 regulates adult neurogenesis in the subventricular zone stem cell niche. Nat. Neurosci. 12, 399–408 (2009). source
    • cites [20] Makeyev, E.V., Zhang, J., Carrasco, M.A. & Maniatis, T. The MicroRNA miR-124 promotes neuronal differentiation by triggering brain-specific alternative pre-mRNA splicing. Mol. Cell 27, 435–448 (2007). source
    • cites [40] Visvanathan, J., Lee, S., Lee, B., Lee, J.W. & Lee, S.K. The microRNA miR-124 antagonizes the anti-neural REST/SCP1 pathway during embryonic CNS development. Genes Dev. 21, 744–749 (2007). source

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

    Premisecitation

    miR-124 can regulate expression of multiple target genes, including those encoding CDKs and MCP-1.

    “It has been shown with human HeLa cells and synoviocytes that miR-124 can regulate expression of multiple target genes, including those encoding CDKs and MCP-1 (refs. 17,42).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [17] Lim, L.P. et al. Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs. Nature 433, 769–773 (2005). source
    • cites [42] Nakamachi, Y. et al. MicroRNA-124a is a key regulator of proliferation and monocyte chemoattractant protein 1 secretion in fibroblast-like synoviocytes from patients with rheumatoid arthritis. Arthritis Rheum. 60, 1294–1304 (2009). source

  • May combine two claims.

    Interpretationown data

    miR-124 directly inhibits expression of C/EBP-α, which results in downregulation of PU.1 and decreases expression of macrophage activation markers CD45, CD11b, F4/80, MHC class II and CD86.

    “We have demonstrated that miR-124 directly inhibits expression of the C/EBP-α transcription factor, which results in downregulation of PU.1, another master regulator of monocytic cell differentiation and decreases expression of the macrophage activation markers CD45, CD11b, F4/80, MHC class II and CD86.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Normal adult microglia do not express C/EBP-α, but this transcription factor can be induced during inflammation.

    “Normal adult microglia do not express C/EBP-α, but this transcription factor can be induced during inflammation38.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Walton, M. et al. CCAAT-enhancer binding proteinα is expressed in activated microglial cells after brain injury. Brain Res. Mol. Brain Res. 61, 11–22 (1998). source

  • May combine two claims.

    Premisecitation

    Quiescent microglia show properties of M2 macrophages and M2 macrophages are crucial for suppression of EAE.

    “These results are consistent with our observations that quiescent microglia show properties of M2 macrophages and that M2 macrophages are crucial for the suppression of EAE45.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [45] Ponomarev, E.D., Maresz, K., Tan, Y. & Dittel, B.N. CNS-derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells. J. Neurosci. 27, 10714–10721 (2007). source

  • May combine two claims.

    Interpretationown data

    miR-124 has a key role in inhibiting macrophage activation and promoting microglial differentiation under physiological conditions in the CNS microenvironment.

    “In summary, our findings demonstrate that miR-124 has a key role in inhibiting macrophage activation and promoting microglial differentiation under physiological conditions in the CNS microenvironment.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    PU.1 controls proliferation of macrophages by upregulating the receptor for M-CSF.

    “Moreover, PU.1 controls proliferation of macrophages by upregulating the receptor for M-CSF34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Celada, A. et al. The transcription factor PU.1 is involved in macrophage proliferation. J. Exp. Med. 184, 61–69 (1996). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    miR-124 has a role in maintaining the quiescent phenotype of microglia in the normal CNS, and this phenotype is driven by paracrine interaction of microglia with local stromal cells.

    “These data demonstrate that miR-124 has a role in maintaining the quiescent phenotype of microglia in the normal CNS, and this phenotype is driven by the paracrine interaction of microglia with local stromal cells.”
    Quote in the paperSubstantial claim
41 of 41

  • The paper relies on this without support.

    There are no markers to distinguish microglia from peripheral macrophages that migrate into the CNS during inflammation.

    “As there are no markers to distinguish microglia from peripheral macrophages that migrate into the CNS during inflammation, we used chimeric mice to discriminate between these populations.”

  • The paper relies on this without support.

    The mechanisms maintaining the unique resting phenotype of microglia in the normal CNS remain unknown.

    “In contrast to other tissue-specific resident macrophages, microglia show a resting phenotype with low expression of both the pan-leukocyte marker CD45 and MHC class II (CD45lowMHC class IIlow) in the normal CNS, but the mechanisms maintaining this unique phenotype remain unknown.”
2 of 2

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?

  • Attenuating PU.1 can potentially restrain microglia-mediated neuroinflammation in various neurological disorders.

    “In various neurological disorders, attenuating PU.1 can potentially restrain microglia-mediated neuroinflammation (16).”

    From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [16]

    The Results (‘miR-124 downregulates C/EBP-α and PU.1’; page unavailable) show that miR-124 indirectly lowers PU.1 and macrophage activation markers. The Results (‘miR-124 inhibits EAE and reduces CNS inflammation’; page unavailable) report reduced activated microglia and CNS inflammation in treated EAE mice. The paper does not establish that attenuating PU.1 itself restrains microglia-mediated neuroinflammation across various neurological disorders; its intervention was miR-124, tested for inflammation in EAE. (LLM, conf=0.83)

    Experimental — accuracy not yet measured

  • The latter role is also found in the model of experimental autoimmune encephalomyelitis (EAE) and optic nerve injury.

    “The latter role is also found in the model of experimental autoimmune encephalomyelitis (EAE) (16) and optic nerve injury (57).”

    From Arresting the bad seed: HDAC3 regulates proliferation of different microglia after ischemic stroke (2024) · cites this paper as [16]

  • In murine microglia, miR-124 downregulates C/EBP-α and subsequently PU.1, inducing microglia quiescence in the central nervous system.

    “In murine microglia, miR-124 downregulates C/EBP-α (and subsequently PU.1, its downstream effector), and thus induces microglia quiescence in the central nervous system.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [232]

  • In experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, symptoms may be completely prevented by miR-124 overexpression.

    “In experimental autoimmune encephalomyelitis, a murine model of multiple sclerosis, symptoms may be completely prevented by miR-124 overexpression [232].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [232]

  • Reducing PU.1 levels through miR124 overexpression decreases expression of TNF-α, iNOS and MHC-II, thereby suppressing neuroinflammatory response in macrophages.

    “Reducing PU.1 levels through miR124 overexpression can decrease expression of TNF-α, iNOS and MHC-II, thereby suppressing neuroinflammatory response in macrophages [491].”

    From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [491]

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Authors
Ponomarev, E. D., Veremeyko, T., Barteneva, N., Krichevsky, A. M., & Weiner, H. L.
Affiliations
  • Brigham and Women's Hospital (US)
  • Harvard University (US)
Corresponding author
  • Krichevsky, Anna M
  • Weiner, Howard L
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2010-12-05
Volume
17
Issue
1
Pages
64-70
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.2266
PMC
PMC3044940
OpenAlex
W2156023352
Semantic Scholar
201a8fce4fc51465ff93360ee1e1b291babf5337
Cited by
787
References
45
Citations by year
2026: 21 · 2025: 40 · 2024: 34 · 2023: 42 · 2022: 44 · 2021: 53 · 2020: 64 · 2019: 54 · 2018: 64 · 2017: 64 · 2016: 66 · 2015: 53 · 2014: 49 · 2013: 73 · 2012: 42
FWCI
25.61
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Institute of Neurological Disorders and Stroke (R01NS071039)
Topics
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Health Sciences › Medicine › Pathology and Forensic Medicine › Multiple Sclerosis Research Studies
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
Keywords
miR-124, experimental autoimmune encephalomyelitis, macrophage deactivation, C/EBPα, PU.1, myelin-specific T cells, neuroinflammation, monocyte activation
MeSH terms
Animals, Brain, Encephalomyelitis, Autoimmune, Experimental, Homeostasis, Humans, Inflammation, Macrophages, Monocytes, Neurons, Microglia, CCAAT-Enhancer-Binding Proteins, MicroRNAs, Mice, Rats

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Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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