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

Zyulina, V.; Yan, K.-K.; Ju, B.; Passegger, C.; Tam-Amersdorfer, C.; Pan, Q.; Sconocchia, T.; Pollack, C.; Shaner, B.; Zebisch, A.; Easton, J.; Yu, J.; Silva, J.; Strobl, H.

doi:10.1101/2020.09.07.285627

bioRxiv · 10.1101/2020.09.07.285627

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

Zyulina, V.·Yan, K.-K.·Ju, B.·Passegger, C.·Tam-Amersdorfer, C.·Pan, Q.·Sconocchia, T.·Pollack, C.·Shaner, B.·Zebisch, A.·Easton, J.·Yu, J.·Silva, J.·Strobl, H.

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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.

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Zyulina, V., Yan, K.-K., Ju, B., Passegger, C., Tam-Amersdorfer, C., Pan, Q., Sconocchia, T., Pollack, C., Shaner, B., Zebisch, A., Easton, J., Yu, J., Silva, J., Strobl, H.. 2020-09-08. miR-424(322) is a molecular switch controlling pro-inflammatory vs anti-inflammatory skin DC subset differentiation by modulating TGF-β signaling. https://doi.org/10.1101/2020.09.07.285627

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