miR-424(322) is a molecular switch controlling pro-inflammatory vs anti-inflammatory skin DC subset differentiation by modulating TGF-β signaling

Abstract

TGF-{beta} family ligands are key regulators of dendritic cell (DC) differentiation and activation. Epidermal Langerhans cells (LCs) require TGF- {beta} family signaling for their differentiation and canonical TGF-{beta}1 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). Among all the miRNAs differentially expressed in LC vs moDCs, we observed miR-424 to be strongly induced during moDC differentiation from monocytes. We discovered that miR-424 is required for moDC differentiation from human and murine precursor cells in vitro and for inflammation-associated moDC in vivo. Mechanistically we found that low levels of miR-424 facilitate TGF-{beta}1-dependent LC differentiation at the expense of moDC differentiation. Loss of miR-424 in monocyte/DC precursors resulted in the induction of TGF-{beta} pathway. Therefore, miR-424 plays a decisive role in anti-inflammatory LC vs pro-inflammatory moDC differentiation from monocytes, and its repression allows TGF-{beta} ligands to promote LC differentiation. Short summaryMonocytes give rise to two distinct DC subsets in skin inflammation, exhibiting opposite roles in inflammation. This study identified miR-424(322) as a molecular switch controlling pro-inflammatory (moDC) vs anti-inflammatory LC subset differentiation by modulating TGF-{beta} signaling.