MicroRNAs of the miR-17~92 family maintain adipose tissue macrophage homeostasis by sustaining IL-10 expression

  1. Xiang Zhang
  2. Jianguo Liu
  3. Li Wu
  4. Xiaoyu Hu  Is a corresponding author
  1. Tsinghua University, China
  2. Saint Louis University, United States

Abstract

Macrophages are critically involved in not only immune and inflammatory responses but also in maintenance of metabolic fitness of organisms. Combined genetic deficiency of three clusters in the miR-17~92 family drastically shifted macrophage phenotypes towards the inflammatory spectrum characterized by heightened production of pro-inflammatory mediator TNF and diminished expression of anti-inflammatory cytokine IL-10. Consequently, macrophages residing in the adipose tissues from myeloid-specific miRNA triple knockout mice spontaneously developed inflammatory phenotypes and displayed alterations of overall physiological conditions as evidenced by obesity and compromised glucose tolerance. Mechanistically, miR-17~92 family miRNAs sustained IL-10 production by promoting transcription of the Fos gene, which is secondary to downregulation of Fos by transcription factor YY1, a direct target of miR-17~92 family miRNAs. Together, these results identified miR-17~92 family miRNAs as crucial regulators of the balance between pro- and anti-inflammatory cytokines and exemplified how macrophage-intrinsic regulatory circuit exerted impactful influence on general physiology.

Data availability

Sequencing data have been deposited in GEO under accession code GSE129613 and GSE158627.

The following data sets were generated

Article and author information

Author details

  1. Xiang Zhang

    Institute for Immunology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  2. Jianguo Liu

    Department of Internal Medicine,, Saint Louis University, Saint Louis, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Li Wu

    Institute for Immunology, Tsinghua University, Beijing, China
    Competing interests
    The authors declare that no competing interests exist.
  4. Xiaoyu Hu

    Institute for Immunology, Tsinghua University, Beijing, China
    For correspondence
    xiaoyuhu@tsinghua.edu.cn
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4289-6998

Funding

National Natural Science Foundation of China (31821003)

  • Xiaoyu Hu

National Natural Science Foundation of China (31725010)

  • Xiaoyu Hu

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments using mice were approved by the Institutional Animal Care and Use Committees at Tsinghua University (Protocol #17-HXY1).

Reviewing Editor

  1. Florent Ginhoux, Agency for Science Technology and Research, Singapore

Publication history

  1. Received: February 2, 2020
  2. Accepted: November 4, 2020
  3. Accepted Manuscript published: November 5, 2020 (version 1)
  4. Version of Record published: November 19, 2020 (version 2)
  5. Version of Record updated: December 14, 2020 (version 3)

Copyright

© 2020, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

Metrics

  • 1,153
    Page views
  • 236
    Downloads
  • 9
    Citations

Article citation count generated by polling the highest count across the following sources: Crossref, PubMed Central, Scopus.

Download links

A two-part list of links to download the article, or parts of the article, in various formats.

Downloads (link to download the article as PDF)

Open citations (links to open the citations from this article in various online reference manager services)

Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)

  1. Xiang Zhang
  2. Jianguo Liu
  3. Li Wu
  4. Xiaoyu Hu
(2020)
MicroRNAs of the miR-17~92 family maintain adipose tissue macrophage homeostasis by sustaining IL-10 expression
eLife 9:e55676.
https://doi.org/10.7554/eLife.55676

Further reading

    1. Cell Biology
    2. Immunology and Inflammation
    Ekaterini Maria Lyras et al.
    Research Article

    The tongue is a unique muscular organ situated in the oral cavity where it is involved in taste sensation, mastication, and articulation. As a barrier organ, which is constantly exposed to environmental pathogens, the tongue is expected to host an immune cell network ensuring local immune defence. However, the composition and the transcriptional landscape of the tongue immune system are currently not completely defined. Here, we characterised the tissue-resident immune compartment of the murine tongue during development, health and disease, combining single-cell RNA-sequencing with in situ immunophenotyping. We identified distinct local immune cell populations and described two specific subsets of tongue-resident macrophages occupying discrete anatomical niches. Cx3cr1+ macrophages were located specifically in the highly innervated lamina propria beneath the tongue epidermis and at times in close proximity to fungiform papillae. Folr2+ macrophages were detected in deeper muscular tissue. In silico analysis indicated that the two macrophage subsets originate from a common proliferative precursor during early postnatal development and responded differently to systemic LPS in vivo. Our description of the under-investigated tongue immune system sets a starting point to facilitate research on tongue immune-physiology and pathology including cancer and taste disorders.

    1. Immunology and Inflammation
    Na Xiao et al.
    Research Article

    B cells contribute to the pathogenesis of polycystic ovary syndrome (PCOS). Clinically, metformin is used to treat PCOS, but it is unclear whether metformin exerts its therapeutic effect by regulating B cells. Here, we showed that the expression level of TNF-α in peripheral blood B cells from PCOS patient was increased. Metformin used in vitro and in vivo was able to reduce the production of TNF-α in B cells from PCOS patient. Administration of metformin improved mouse PCOS phenotypes induced by dehydroepiandrosterone (DHEA) and also inhibited TNF-α expression in splenic B cells. Further, metformin induced metabolic reprogramming of B cells in PCOS patients, including the alteration in mitochondrial morphology, the decrease in mitochondrial membrane potential, ROS production and glucose uptake. In DHEA-induced mouse PCOS model, metformin altered metabolic intermediates in splenic B cells. Moreover, the inhibition of TNF-α expression and metabolic reprogramming in B cells of PCOS patients and mouse model by metformin were associated with decreased mTOR phosphorylation. Together, TNF-α-producing B cells are involved in the pathogenesis of PCOS, and metformin inhibits mTOR phosphorylation and affects metabolic reprogramming, thereby inhibiting TNF-α expression in B cells, which may be a new mechanism of metformin in the treatment of PCOS.