1. The miR-424(322)/503 gene cluster regulates pro- versus anti-inflammatory skin DC subset differentiation by modulating TGF-β signaling
- Author
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John Easton, Elke Schwarzenberger, Tommaso Sconocchia, Christian Pollack, Qingfei Pan, Armin Zebisch, Jose M. Silva, Koon-Kiu Yan, Bensheng Ju, Carmen Tam-Amersdorfer, Herbert Strobl, Victoria Zyulina, Bridget Shaner, Christina Passegger, and Jiyang Yu
- Subjects
0301 basic medicine ,Anti-Inflammatory Agents ,Inflammation ,General Biochemistry, Genetics and Molecular Biology ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Transforming Growth Factor beta ,microRNA ,Gene cluster ,Langerhans cell differentiation ,medicine ,Animals ,Humans ,Interleukin 4 ,integumentary system ,Chemistry ,Monocyte ,Cell Differentiation ,Dendritic cell ,Cell biology ,MicroRNAs ,030104 developmental biology ,medicine.anatomical_structure ,Langerhans Cells ,Multigene Family ,medicine.symptom ,030217 neurology & neurosurgery ,Signal Transduction ,Transforming growth factor - Abstract
Transforming growth factor β (TGF-β) family ligands are key regulators of dendritic cell (DC) differentiation and activation. Epidermal Langerhans cells (LCs) require TGF-β family signaling for their differentiation, and canonical TGF-β1 signaling secures a non-activated LC state. LCs reportedly control skin inflammation and are replenished from peripheral blood monocytes, which also give rise to pro-inflammatory monocyte-derived DCs (moDCs). By studying mechanisms in inflammation, we previously screened LCs versus moDCs for differentially expressed microRNAs (miRNAs). This revealed that miR-424/503 is the most strongly inversely regulated (moDCs > LCs). We here demonstrate that miR-424/503 is induced during moDC differentiation and promotes moDC differentiation in human and mouse. Inversely, forced repression of miR-424 during moDC differentiation facilitates TGF-β1-dependent LC differentiation. Mechanistically, miR-424/503 deficiency in monocyte/DC precursors leads to the induction of TGF-β1 response genes critical for LC differentiation. Therefore, the miR-424/503 gene cluster plays a decisive role in anti-inflammatory LC versus pro-inflammatory moDC differentiation from monocytes.
- Published
- 2021
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