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Cited by 103Neuroinflammation and Neurodegeneration MechanismsMicroRNA in disease regulationInflammasome and immune disorders

The p53 Transcription Factor Modulates Microglia Behavior through MicroRNA-Dependent Regulation of c-Maf

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Su, Wei, Hopkins, Stephanie, Nesser, Nicole K, Sopher, Bryce, Silvestroni, Aurelio, Ammanuel, Simon, Jayadev, Suman, Möller, Thomas +2 more·2014·The Journal of Immunology
DOI 10.4049/jimmunol.1301397PMC PMC4195583
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Abstract

Neuroinflammation occurs in acute and chronic CNS injury, including stroke, traumatic brain injury, and neurodegenerative diseases. Microglia are specialized resident myeloid cells that mediate CNS innate immune responses. Disease-relevant stimuli, such as reactive oxygen species (ROS), can influence microglia activation. Previously, we observed that p53, a ROS-responsive transcription factor, modulates microglia behaviors in vitro and in vivo, promoting proinflammatory functions and suppressing downregulation of the inflammatory response and tissue repair. In this article we describe a novel mechanism by which p53 modulates the functional differentiation of microglia both in vitro and in vivo. Adult microglia from p53-deficient mice have increased expression of the anti-inflammatory transcription factor c-Maf. To determine how p53 negatively regulates c-Maf, we examined the impact of p53 on known c-Maf regulators. MiR-155 is a microRNA that targets c-Maf. We observed that cytokine-induced expression of miR-155 was suppressed in p53-deficient microglia. Furthermore, Twist2, a transcriptional activator of c-Maf, is increased in p53-deficient microglia. We identified recognition sites in the 3′ untranslated region of Twist2 mRNA that are predicted to interact with two p53-dependent microRNAs: miR-34a and miR-145. In this article, we demonstrate that miR-34a and -145 are regulated by p53 and negatively regulate Twist2 and c-Maf expression in microglia and the RAW macrophage cell line. Taken together, these findings support the hypothesis that p53 activation induced by local ROS or accumulated DNA damage influences microglia functions and that one specific molecular target of p53 in microglia is c-Maf.

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Crossref · 10.4049/jimmunol.1301397

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  • miR-155 targets the anti-inflammatory transcription factor c-Maf for degradation in microglia.

    “Previously, we demonstrated that miR-155 targets the anti-inflammatory transcription factor c-Maf for degradation in microglia [25].”

    From Microglia specific deletion of miR-155 in Alzheimer’s disease mouse models reduces amyloid-β pathology but causes hyperexcitability and seizures (2023) · cites this paper as [25]

    The Results section reports higher c-Maf mRNA in miR-155-knockout microglia, and the Discussion says miR-155 directly targets c-Maf and suppresses its expression. Our copy does not establish that c-Maf is degraded, rather than downregulated, so that mechanism is not supported. No page number is available in our copy. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Stimulation with IFNγ, IL-1α, and MARCO (but not IL-1β) activates p53, upregulates miR-155, which downregulates c-Maf, inducing an inflammatory response.

    “Su et al. demonstrated that stimulation with IFNγ, IL-1α and MARCO, but not with IL-1β, leads to activation of p53, and subsequent upregulation of miR-155, which in turn downregulates c-Maf, thus inducing an inflammatory response.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [230]

    The Results section reports that IFNγ induces miR-155 in a p53-dependent manner and that miR-155 suppresses c-Maf. But it treats IL-1α, MARCO, and IL-1β as genes measured after IFNγ treatment, not as stimuli: IL-1α and MARCO showed miR-155-dependent induction, whereas IL-1β did not. The cited paper therefore supports the pathway but not the claim's list of activating stimuli. (LLM, conf=0.89)

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Cited by

Sorted by citations

Authors
Su, W., Hopkins, S., Nesser, N. K., Sopher, B., Silvestroni, A., Ammanuel, S., Jayadev, S., Möller, T., Weinstein, J., & Garden, G. A.
Affiliations
University of Washington (US)
Corresponding author
  • Su, Wei
  • Hopkins, Stephanie
  • Sopher, Bryce
  • Silvestroni, Aurelio
  • Ammanuel, Simon
  • Jayadev, Suman
  • Weinstein, Jonathan
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2014-01-01
Volume
192
Issue
1
Pages
358-366
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.1301397
PMC
PMC4195583
OpenAlex
W1858233563
Cited by
103
References
9
Citations by year
2026: 4 · 2025: 6 · 2024: 12 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 8 · 2019: 9 · 2018: 5 · 2017: 9 · 2016: 10 · 2015: 14 · 2014: 2
FWCI
4.86
Type
journal article
Language
en
Open access
Licence
academic.oup.com/pages/standard-publication-reuse-rights (vor)
Locations
  • The Journal of Immunology (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institute of Neurological Disorders and Stroke (R01NS073848, R01NS076620, R03NS070141, R03NS70141, R21NS062269)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (P30HD02274, U54HD083091, P30HD002274)
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
p53, microglia, c-Maf, microRNA, miR-155, miR-34a, miR-145, TWIST2, reactive oxygen species, neuroinflammation, microglial activation, 3' untranslated region, DNA damage, RAW 264.7 macrophages
MeSH terms
Animals, Cell Line, Brain Ischemia, Disease Models, Animal, Gene Expression Regulation, Humans, Male, Models, Biological, Phenotype, Repressor Proteins, Tumor Suppressor Protein p53, Microglia, Mice, Knockout, MicroRNAs, Proto-Oncogene Proteins c-maf, Mice, Twist-Related Protein 1

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