Toll‐like receptor (TLR) stimulation induces innate immune responses involved in many inflammatory disorders including psoriasis. Although activation of the AP‐1 transcription factor complex is common in TLR signaling, the specific involvement and induced targets remain poorly understood. Here, we investigated the role of c‐Jun/AP‐1 protein in skin inflammation following TLR7 activation using human psoriatic skin, dendritic cells (DC), and genetically engineered mouse models. We show that c‐Jun regulates CCL2 production in DCs leading to impaired recruitment of plasmacytoid DCs to inflamed skin after treatment with the TLR7/8 agonist Imiquimod. Furthermore, deletion of c‐Jun in DCs or chemical blockade of JNK/c‐Jun signaling ameliorates psoriasis‐like skin inflammation by reducing IL‐23 production in DCs. Importantly, the control of IL‐23 and CCL2 by c‐Jun is most pronounced in murine type‐2 DCs. CCL2 and IL‐23 expression co‐localize with c‐Jun in type‐2/inflammatory DCs in human psoriatic skin and JNK‐AP‐1 inhibition reduces the expression of these targets in TLR7/8‐stimulated human DCs. Therefore, c‐Jun/AP‐1 is a central driver of TLR7‐induced immune responses by DCs and JNK/c‐Jun a potential therapeutic target in psoriasis.

Background: Bone morphogenetic proteins (BMPs) are members of the TGF-b family that signal via the BMP receptor (BMPR) signaling cascade, distinct from canonical TGF-b signaling. BMP downstream signaling is strongly induced within epidermal keratinocytes in cutaneous psoriatic lesions, and BMP7 instructs monocytic cells to acquire characteristics of psoriasis-associated Langerhans dendritic cells (DCs). Regulatory T (Treg)-cell numbers strongly increase during psoriatic skin inflammation and were recently shown to limit psoriatic skin inflammation. However, the factors mediating Treg-cell accumulation in psoriatic skin currently remain unknown. Objective: We sought to investigate the role of BMP signaling in Treg-cell accumulation in psoriasis. Methods: The following methods were used: immunohistology of patients and healthy controls; ex vivo models of Treg-cell generation in the presence or absence of Langerhans cells; analysis of BMP versus canonical TGF-b signaling in DCs and Treg cells; and modeling of psoriatic skin inflammation in mice lacking the BMPR type 1a in CD11c 1 cells. Results: We here demonstrated a positive correlation between Treg-cell numbers and epidermal BMP7 expression in cutaneous psoriatic lesions and show that unlike Treg cells from healthy skin, a portion of inflammation-associated Treg cells exhibit constitutive-active BMP signaling. We further found

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The miR-424(322)/503 gene cluster regulates proversus anti-inflammatory skin DC subset differentiation by modulating TGF-b signaling Graphical abstract Highlights d miR-424(322)/503 promotes inflammatory moDC differentiation in human and mouse d miR-424(322)/503 acts as a molecular switch between moDC and LC fates of monocytes d miR-424(322)/503 knockout is associated with enrichment of TGF-b1 signaling genes

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). 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-β1-dependent LC differentiation at the expense of moDC differentiation. Loss of miR-424 in monocyte/DC precursors resulted in the induction of TGF-β pathway. Therefore, miR-424 plays a decisive role in anti-inflammatory LC vs pro-inflammatory moDC differentiation from monocytes, and its repression allows TGF-β 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-β signaling.