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Cited by 35MicroRNA in disease regulationNeuroinflammation and Neurodegeneration MechanismsBacterial Infections and Vaccines

miR-155 and miR-146a collectively regulate meningitic Escherichia coli infection-mediated neuroinflammatory responses

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Yang, Bo, Yang, Ruicheng, Xu, Bojie, Fu, Jiyang, Qu, Xinyi, Li, Liang, Dai, Menghong, Tan, Chen +2 more·2021·Journal of Neuroinflammation
DOI 10.1186/s12974-021-02165-4PMC PMC8120916
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Abstract

Background: Escherichia coli is the most common Gram-negative bacterium causing meningitis, and E. coli meningitis is associated with high mortality and morbidity throughout the world. Our previous study showed that E. coli can colonize the brain and cause neuroinflammation. Increasing evidence supports the involvement of miRNAs as key regulators of neuroinflammation. However, it is not clear whether these molecules participate in the regulation of meningitic E. coli-mediated neuroinflammation. Methods: The levels of miR-155 and miR-146a, as well as their precursors, in E. coli-infected astrocytes were measured using quantitative real-time PCR (qPCR). Overexpression and knockdown studies of miR-155 and miR-146a were performed to observe the effects on bacterial loads, cytokines, chemokines, and NF-κB signaling pathways. Bioinformatics methods were utilized to predict the target genes, and these target genes were validated using qPCR, Western blotting, and luciferase reporter system. In vivo knockdown of miR-155 and miR-146a was carried out to observe the effects on bacterial loads, inflammatory genes, astrocyte activation, microglia activation, and survival in a mouse model. Results: The levels of miR-155, miR-146a, and their precursors were significantly increased in astrocytes during E. coli infection. miR-155 and miR-146a were induced by the NF-κB-p65 signaling pathway upon infection. Overexpressing and inhibiting miR-155 and miR-146a in astrocytes did not affect the bacterial loads. Further, the in vitro overexpression of miR-155 and miR-146a suppressed the E. coli-induced inflammatory response, whereas the inhibition of miR-155 and miR-146a enhanced it. Mechanistically, miR-155 inhibited TAB2, and miR-146a targeted IRAK1 and TRAF6; therefore, they functioned collaboratively to modulate TLR-mediated NF-κB signaling. In addition, both miR-155 and miR-146a could regulate the EGFR–NF-κB signaling pathway. Finally, the in vivo suppression of E. coli-induced miR-155 and miR-146a further promoted the production of inflammatory cytokines, aggravated astrocyte and microglia activation, and decreased mouse survival time, without affecting the bacterial loads in the blood and brain. Conclusions: E. coli infection induced miR-155 and miR-146a, which collectively regulated bacteria-triggered neuroinflammatory responses through negative feedback regulation involving the TLR-mediated NF-κB and EGFR–NF-κB signaling pathways, thus protecting the central nervous system from further neuroinflammatory damage.

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  • Suppression of miR-146a and miR-155 upon E. coli infection aggravates astrocyte and microglia activation and decreases mouse survival time without affecting bacterial loads.

    “Experimental suppression of these microRNAs upon E. coli infection aggravated astrocyte and microglia activation and decreased mouse survival time without affecting bacterial loads [236].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [236]

  • miR-146a and miR-155 are upregulated in E. coli-infected astrocytes; miR-146a targets IRAK1 and TRAF6, miR-155 targets TAB2, and they collectively inhibit EGFR-NF-κB signaling.

    “Both miR-146a and miR-155 are upregulated in E. coli-infected astrocytes, taking part in fine-tuning of inflammatory response by targeting IRAK1 and TRAF6 (miR-146a), and TAB2 (miR-155), and collectively inhibiting the EGFR–NF-κB signaling pathway.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [236]

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Cited by

Sorted by citations

Authors
Yang, B., Yang, R., Xu, B., Fu, J., Qu, X., Li, L., Dai, M., Tan, C., Chen, H., & Wang, X.
Affiliations
Huazhong Agricultural University (CN)
Corresponding author
Wang, Xiangru
ORCID
Venue
Journal of Neuroinflammation
Publisher
Springer Science and Business Media LLC
Published
2021-05-13
Volume
18
Issue
1
Pages
114-114
ISSN
1742-2094 (ISSN-L)
DOI
10.1186/s12974-021-02165-4
PMC
PMC8120916
OpenAlex
W3161403622
Cited by
35
References
5
Citations by year
2026: 7 · 2025: 7 · 2024: 8 · 2023: 4 · 2022: 9
FWCI
2.09
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Neuroinflammation (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Natural Science Foundation of China (31772736)
  • National Key R&D Program of China (2016YFD0500406)
  • the Fundamental Research Funds for the Central Universities (2662018PY032)
  • the earmarked fund for China Agriculture Research System (CARS-35)
  • the Outstanding youth project of Natural Science Foundation in Hubei Province (2018CFA070)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
  • Life Sciences › Immunology and Microbiology › Microbiology › Bacterial Infections and Vaccines
Keywords
miR-146a, meningitis, Escherichia coli, neuroinflammation, microRNA, astrocytes, NF-κB signaling, TAB2, IRAK1, TRAF6, EGFR signaling, Toll-like receptor signaling, microglial activation, bacterial clearance, mouse model, miRNA target genes, neuroprotection, neurodegeneration
MeSH terms
Antagomirs, Animals, Astrocytes, Cell Line, Escherichia coli, Inflammation, Signal Transduction, NF-kappa B, Meningitis, Escherichia coli, MicroRNAs, TNF Receptor-Associated Factor 6, Adaptor Proteins, Signal Transducing, Mice, Interleukin-1 Receptor-Associated Kinases

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