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.
Article and author information
Author details
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
- Florent Ginhoux, Agency for Science Technology and Research, Singapore
Publication history
- Received: February 2, 2020
- Accepted: November 4, 2020
- Accepted Manuscript published: November 5, 2020 (version 1)
- Version of Record published: November 19, 2020 (version 2)
- 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.
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