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Cited by 581Immune Response and InflammationMicroRNA in disease regulationNeuroinflammation and Neurodegeneration Mechanisms

The Kinase Akt1 Controls Macrophage Response to Lipopolysaccharide by Regulating MicroRNAs

Open access
Androulidaki, Ariadne, Iliopoulos, Dimitrios, Arranz, Alicia, Doxaki, Christina, Schworer, Steffen, Zacharioudaki, Vassiliki, Margioris, Andrew N., Tsichlis, Philip N. +1 more·2009·Immunity
DOI 10.1016/j.immuni.2009.06.024PMC PMC2865583
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Abstract

MicroRNAs regulated by lipopolysaccharide (LPS) target genes that contribute to the inflammatory phenotype. Here, we showed that the protein kinase Akt1, which is activated by LPS, positively regulated miRNAs let-7e and miR-181c but negatively regulated miR-155 and miR-125b. In silico analyses and transfection studies revealed that let-7e repressed Toll-like receptor 4 (TLR4), whereas miR-155 repressed SOCS1, two proteins critical for LPS-driven TLR signaling, which regulate endotoxin sensitivity and tolerance. As a result, Akt1(-/-) macrophages exhibited increased responsiveness to LPS in culture and Akt1(-/-) mice did not develop endotoxin tolerance in vivo. Overexpression of let-7e and suppression of miR-155 in Akt1(-/-) macrophages restored sensitivity and tolerance to LPS in culture and in animals. These results indicate that Akt1 regulates the response of macrophages to LPS by controlling miRNA expression.

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Crossref · 10.1016/j.immuni.2009.06.024

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  • Macrophage development is regulated by miR-155 and miR-146a expression.

    “Macrophage development is regulated by miR-155 and miR-146a expression [54,55,56,57].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [57]

    The Introduction links miR-155 to destabilization of PU.1, which it identifies as a key mediator of monocyte/macrophage differentiation. But the paper’s Results and Discussion focus on macrophage responses to LPS, not macrophage development, and the retrieved passages do not address miR-146a. (LLM, conf=0.79)

    Experimental — accuracy not yet measured

  • let-7e targets TLR4 and miR-155 targets SOCS1, leading to LPS tolerance.

    “They showed that let-7e targets TLR4 and miR-155 targets SOCS1, thus leading to LPS tolerance [57].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [57]

    Results §3 confirms that let-7e targets TLR4 and miR-155 targets SOCS1. But Results §§4 and 6 do not support the claim that both targeting actions lead to LPS tolerance: miR-155 increased the LPS response, while mice became tolerant after receiving macrophages treated with let-7e and an inhibitor of miR-155. Page numbers are unavailable in our copy. (LLM, conf=0.90)

    Experimental — accuracy not yet measured

  • Akt1 upregulates let-7e and miR-181c and downregulates miR-155 and miR-125b.

    “Protein kinase Akt1 upregulates let-7e and miR-181c but downregulates miR-155 and miR-125b.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [57]

    The Results (section 1) support Akt1 increasing let-7e and miR-181c and reducing miR-155 in LPS-stimulated macrophages. They also report that active Akt1 increases the LPS-induced suppression of miR-125b, but has no effect on its basal level. Thus the unqualified claim that Akt1 downregulates miR-125b omits a condition that matters. (LLM, conf=0.94)

    Experimental — accuracy not yet measured

  • miR-155 is repressed by IL-10 signaling through STAT3.

    “Interestingly, miR-155 is also repressed by IL-10 signaling through STAT3 [57].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [57]

    The Discussion reports that Akt1 negatively regulates miR-155 in LPS-activated macrophages. The Introduction mentions STAT signalling only in connection with SOCS1, a target of miR-155. Neither passage addresses whether IL-10 represses miR-155 through STAT3; searches for IL-10, STAT3 and that regulatory pathway found no supporting passage in our copy. (LLM, conf=0.75)

    Experimental — accuracy not yet measured

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Authors
Androulidaki, A., Iliopoulos, D., Arranz, A., Doxaki, C., Schworer, S., Zacharioudaki, V., Margioris, A. N., Tsichlis, P. N., & Tsatsanis, C.
Affiliations
  • University of Crete (GR)
  • Harvard University (US)
  • Tufts Medical Center (US)
Corresponding author
Tsatsanis, Christos
ORCID
Venue
Immunity
Publisher
Elsevier BV
Published
2009-08
Volume
31
Issue
2
Pages
220-231
ISSN
1074-7613 (ISSN-L)
DOI
10.1016/j.immuni.2009.06.024
PMC
PMC2865583
OpenAlex
W2067647130
Cited by
581
References
46
Citations by year
2026: 14 · 2025: 13 · 2024: 17 · 2023: 22 · 2022: 28 · 2021: 26 · 2020: 27 · 2019: 25 · 2018: 42 · 2017: 42 · 2016: 50 · 2015: 47 · 2014: 45 · 2013: 54 · 2012: 53
FWCI
18.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Immunity (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Institutes of Health
  • National Cancer Institute (R01CA057436, N02 CO041101, 2-CO-41101)
Topics
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
AKT1, macrophages, lipopolysaccharide, microRNA, let-7e, miR-155, miR-181c, miR-125b, TLR4, SOCS1, endotoxin tolerance, endotoxin sensitivity, LPS signaling, inflammation
MeSH terms
Suppressor of Cytokine Signaling 1 Protein, Animals, Cell Line, Immune Tolerance, Lipopolysaccharides, Macrophages, Mice, Inbred C57BL, Mice, Knockout, MicroRNAs, Suppressor of Cytokine Signaling Proteins, Proto-Oncogene Proteins c-akt, Toll-Like Receptor 4, Mice

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