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Cited by 275MicroRNA in disease regulationNF-κB Signaling PathwaysImmune Response and Inflammation

An NF-κB-microRNA regulatory network tunes macrophage inflammatory responses

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Mann, Mati, Mehta, Arnav, Zhao, Jimmy L., Lee, Kevin, Marinov, Georgi K., Garcia-Flores, Yvette, Lu, Li-Fan, Rudensky, Alexander Y. +1 more·2017·Nature Communications
DOI 10.1038/s41467-017-00972-zPMC PMC5636846
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Abstract

The innate inflammatory response must be tightly regulated to ensure effective immune protection. NF-κB is a key mediator of the inflammatory response, and its dysregulation has been associated with immune-related malignancies. Here, we describe a miRNA-based regulatory network that enables precise NF-κB activity in mouse macrophages. Elevated miR-155 expression potentiates NF-κB activity in miR-146a-deficient mice, leading to both an overactive acute inflammatory response and chronic inflammation. Enforced miR-155 expression overrides miR-146a-mediated repression of NF-κB activation, thus emphasizing the dominant function of miR-155 in promoting inflammation. Moreover, miR-155-deficient macrophages exhibit a suboptimal inflammatory response when exposed to low levels of inflammatory stimuli. Importantly, we demonstrate a temporal asymmetry between miR-155 and miR-146a expression during macrophage activation, which creates a combined positive and negative feedback network controlling NF-κB activity. This miRNA-based regulatory network enables a robust yet time-limited inflammatory response essential for functional immunity.

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  • Increased levels of miR-155 promotes pro-inflammatory cytokine secretion by targeting SOCS1 message for degradation and downregulating anti-inflammatory cytokines that act via JAK/STAT pathway and NF-kB signaling.

    “Increased levels of miR-155 promotes pro-inflammatory cytokine secretion by targeting the Suppressor of Cytokine Signaling 1 (SOCS1) message for degradation and downregulating anti-inflammatory cytokines that act via the JAK/STAT pathway [27, 47] and NF-kB signaling [48].”

    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 [48]

    The Results sections on miR-155 overexpression and SHIP1/SOCS1 repression (page unavailable) support the NF-κB portion cited to this paper: elevated miR-155 enhances NF-κB activity, and the paper identifies SHIP1 downregulation as a mechanism. The paper also reports repression of SOCS1, but it does not show that SOCS1-message degradation or downregulation of anti-inflammatory cytokines causes the NF-κB effect; in its experiments, SOCS1 chiefly affected cell proliferation. (LLM, conf=0.86)

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Sorted by citations

Authors
Mann, M., Mehta, A., Zhao, J. L., Lee, K., Marinov, G. K., Garcia-Flores, Y., Lu, L.-F., Rudensky, A. Y., & Baltimore, D.
Affiliations
  • California Institute of Technology (US)
  • Memorial Sloan Kettering Cancer Center (US)
  • University of California San Diego (US)
Corresponding author
  • Mann, Mati
  • Baltimore, David
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2017-10-11
Volume
8
Issue
1
Pages
851-851
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-017-00972-z
PMC
PMC5636846
OpenAlex
W2762253335
Cited by
275
References
8
Citations by year
2026: 33 · 2025: 32 · 2024: 32 · 2023: 26 · 2022: 34 · 2021: 32 · 2020: 29 · 2019: 34 · 2018: 23
FWCI
7.90
Type
journal article
Language
en
Update notices
correction (2018-08-16)
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • CaltechAUTHORS (California Institute of Technology) (submittedVersion, cc-by)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • California Institute of Technology
  • National Institutes of Health
  • National Cancer Institute (F30CA183220)
  • National Institute of Allergy and Infectious Diseases (R01AI108651, R01AI079243)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Keywords
NF-κB signaling, miRNA regulatory network, miR-155, miR-146a, macrophage activation, innate immunity, inflammation, positive and negative feedback, chronic inflammation, acute inflammatory response, transcriptional regulation
MeSH terms
Suppressor of Cytokine Signaling 1 Protein, Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases, Animals, Humans, Macrophages, Mice, Inbred C57BL, Phenotype, NF-kappa B, Mice, Knockout, MicroRNAs, HEK293 Cells

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