Otto Loewi Research Center, Chair of Immunology and Pathophysiology, Medical University of Graz, 8010 Graz, Austria.
Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, TN 38105-3678, USA.
Cell Rep. 2021 Apr 27;35(4):109049. doi: 10.1016/j.celrep.2021.109049.
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.
转化生长因子 β（TGF-β）家族配体是树突状细胞（DC）分化和激活的关键调节剂。表皮朗格汉斯细胞（LCs）分化需要 TGF-β 家族信号，而经典的 TGF-β1 信号则确保了非激活的 LC 状态。LCs 据报道可控制皮肤炎症，并由外周血单核细胞补充，这些细胞也可产生促炎的单核细胞衍生的 DC（moDC）。通过研究炎症中的机制，我们之前在 LCs 和 moDC 之间筛选了差异表达的 microRNAs（miRNAs）。结果显示，miR-424/503 的调控最为显著（moDCs > LCs）。我们在此证明，miR-424/503 在 moDC 分化过程中被诱导，并促进人和小鼠的 moDC 分化。相反，在 moDC 分化过程中强制抑制 miR-424 可促进 TGF-β1 依赖性 LC 分化。从机制上讲，单核细胞/DC 前体中的 miR-424/503 缺失会诱导对 LC 分化至关重要的 TGF-β1 反应基因。因此，miR-424/503 基因簇在抗炎 LC 与促炎 moDC 从单核细胞分化中起着决定性作用。
