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.
Sequencing data have been deposited in GEO under accession code GSE129613 and GSE158627.
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) miceNCBI Gene Expression Omnibus, GSE129613.
- Xiaoyu Hu
- Xiaoyu Hu
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: All experiments using mice were approved by the Institutional Animal Care and Use Committees at Tsinghua University (Protocol #17-HXY1).
- Florent Ginhoux, Agency for Science Technology and Research, Singapore
© 2020, Zhang et al.
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