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Cited by 81MicroRNA in disease regulationImmune Response and InflammationSepsis Diagnosis and Treatment

miR-15a/16 Regulates Macrophage Phagocytosis after Bacterial Infection

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Moon, Hyung-Geun, Yang, Jincheng, Zheng, Yijie, Jin, Yang·2014·The Journal of Immunology
DOI 10.4049/jimmunol.1401372PMC PMC4216178
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Abstract

Bacterial infection and its associated sepsis are devastating clinical entities that lead to high mortality and morbidity in critically ill patients. Phagocytosis, along with other innate immune responses, exerts crucial impacts on the outcomes of these patients. MicroRNAs (miRNAs) are a novel class of regulatory noncoding RNAs that target specific mRNAs for modulation of translation and expression of a targeted protein. The roles of miRNAs in host defense against bacterial sepsis remain unclear. We found that bacterial infections and/or bacterial-derived LPS enhanced the level of miR-15a/16 in bone marrow–derived macrophages (BMDMs). Deletion of miR-15a/16 (miR-15a/16−/−) in myeloid cells significantly decreased the bacterial infection–associated mortality in sepsis mouse models. Moreover, miR-15a/16 deficiency (miR-15a/16−/−) resulted in augmented phagocytosis and generation of mitochondrial reactive oxygen species in BMDMs. Supportively, overexpression of miR-15a/16 using miRNA mimics led to decreased phagocytosis and decreased generation of mitochondrial reactive oxygen species. Mechanistically, deletion of miR-15a/16 upregulated the expression of TLR4 via targeting the principle transcriptional regulator PU.1 locating on the promoter region of TLR4, and further modulated the downstream signaling molecules of TLR4, including Rho GTPase Cdc 42 and TRAF6. In addition, deficiency of miR-15a/16 also facilitated TLR4-mediated proinflammatory cytokine/chemokine release from BMDMs at the initial phase of infections. Taken together, miR-15a/16 altered phagocytosis and bacterial clearance by targeting, at least partially, on the TLR4-associated pathways, subsequently affecting the survival of septic mice.

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  • These pro-inflammatory effects stimulate E. coli uptake and mitochondrial ROS generation.

    “These pro-inflammatory effects stimulate both E. coli uptake and generation of mitochondrial ROS [113].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [113]

    The Results (page not provided) report greater E. coli uptake and mitochondrial ROS generation in miR-15a/16-deficient macrophages. The Discussion (page not provided) also reports increased pro-inflammatory cytokines and chemokines, but does not show that those pro-inflammatory effects stimulate either uptake or ROS generation; it discusses other pathways for those outcomes. (LLM, conf=0.86)

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  • Bacterial infection and LPS induce miR-15a/16.

    “Both bacterial infection and LPS itself induce miR-15a/16.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [113]

  • In mice, miR-15a/16 knockout derepresses PU.1, upregulating TLR4 and modulating Cdc42 and TRAF6.

    “In mice miR-15a/16 knock-out derepresses PU.1, which upregulates TLR4, further modulating Rho GTPase Cdc 42 and TRAF6.”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [113]

  • Other miRNAs that are highly conserved in metazoans or known to be expressed in myeloid cells, including miR-191-5p, miR-15a-5p, miR-206, miR-335-5p, and miR-339-3p, showed moderate expression levels.

    “Other miRNAs that are highly conserved in metazoans or known to be expressed in myeloid cells, including miR-191-5p (ref. 53), miR-15a-5p (ref. 54), miR-206 (ref. 55), miR-335-5p (ref. 56), and miR-339-3p (ref. 56), were included and used as positive controls, and showed moderate expression levels.”

    From An integrated expression atlas of miRNAs and their promoters in human and mouse (2017) · cites this paper as [54]

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Research works printed but not linked: 1

  1. [43]McClure C Brudecki L Ferguson DA Yao ZQ Moorman JP McCall CE El Gazzar M 2014 miR-21 and miR-181b couple with NFI-A to generate MDSCs and promote immunosuppression in late sepsis Infect Immun pii IAI.01495 14 PMC4187818 24980967

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Authors
Moon, H.-G., Yang, J., Zheng, Y., & Jin, Y.
Affiliations
Brigham and Women's Hospital (US)
ORCID
Venue
The Journal of Immunology
Publisher
Oxford University Press (OUP)
Published
2014-11-01
Volume
193
Issue
9
Pages
4558-4567
ISSN
  • 0022-1767 (ISSN-L)
  • 1550-6606
DOI
10.4049/jimmunol.1401372
PMC
PMC4216178
OpenAlex
W1575896755
Cited by
81
References
49
Citations by year
2026: 1 · 2025: 3 · 2024: 5 · 2023: 6 · 2022: 7 · 2021: 11 · 2020: 6 · 2019: 8 · 2018: 11 · 2017: 8 · 2016: 12 · 2015: 3
FWCI
2.46
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)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • National Heart, Lung, and Blood Institute (R01HL102076)
  • National Institute of General Medical Sciences (R01GM111313)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
  • Health Sciences › Medicine › Epidemiology › Sepsis Diagnosis and Treatment
Keywords
microRNA, macrophage phagocytosis, bacterial sepsis, TLR4 signaling, PU.1, Cdc42, TRAF6, mitochondrial reactive oxygen species, bone marrow-derived macrophages, inflammatory cytokines, chemokines, bacterial clearance, innate immunity
MeSH terms
Animals, Bacterial Infections, Cell Survival, Disease Models, Animal, Lipopolysaccharides, Macrophages, Mitochondria, Phagocytosis, Signal Transduction, Gene Expression, Cytokines, Gene Deletion, Mice, Knockout, Sepsis, MicroRNAs, Toll-Like Receptor 4, Mice

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