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

Abstract
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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

1. Xiang Zhang
(2019) RNAseq to profile transcriptomes in bone marrow-derived macrophages from TKO(mir-106a~363-/- mir-106b~25-/- mir-17~92flox/flox Lyz2-Cre) and WT(Lyz2-Cre) mice
NCBI Gene Expression Omnibus, GSE129613.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE129613
1. Xiang Zhang
(2020) RNAseq to profile transcriptomes in adipose tissue macrophages (ATMs) from TKO(mir-106a~363-/- mir-106b~25-/- mir-17~92flox/flox Lyz2-Cre) and WT(Lyz2-Cre) mice fed with regular chow diet or high fat diet
NCBI Gene Expression Omnibus, GSE158627.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE158627

Article and author information

Author details

Xiang Zhang

Institute for Immunology, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
Jianguo Liu

Department of Internal Medicine,, Saint Louis University, Saint Louis, United States

Competing interests
The authors declare that no competing interests exist.
Li Wu

Institute for Immunology, Tsinghua University, Beijing, China

Competing interests
The authors declare that no competing interests exist.
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.

"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).

Copyright

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.