The miR-424(322)/503 gene cluster regulates pro- versus anti-inflammatory skin DC subset differentiation by modulating TGF-β signaling

• DOI: 10.1016/j.celrep.2021.109049
• Publication Date: 2021-04-27T16:24:43Z
• Authors: Victoria Zyulina; Koon-Kiu Yan; Bensheng Ju; Elke Schwarzenberger; Christina Passegger; Carmen Tam-Amersd...; Qingfei Pan; Tommaso Sconocchia; Christian Pollack; Bridget Shaner; Armin Zebisch; John Easton; Jiyang Yu; Jose M. Silva; Herbert Strobl
• Keywords: Mice; MicroRNAs; 0303 health sciences; 03 medical and health sciences; Transforming Growth Factor beta; Langerhans Cells; Multigene Family; Anti-Inflammatory Agents; Animals; Humans; Cell Differentiation; Signal Transduction

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.