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Psoriatic skin inflammation is promoted by c‐Jun/AP‐1‐dependent CCL2 and IL‐23 expression in dendritic cells
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Psoriatic skin inflammation is promoted by c‐Jun/AP‐1‐dependent CCL2 and IL‐23 expression in dendritic cells
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Psoriatic skin inflammation is promoted by c‐Jun/AP‐1‐dependent CCL2 and IL‐23 expression in dendritic cells
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Journal Article
Psoriatic skin inflammation is promoted by c‐Jun/AP‐1‐dependent CCL2 and IL‐23 expression in dendritic cells
2021
Overview
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.
Synopsis
Based on genetically engineered mouse models (GEMMs) and human psoriasis biopsies, this study suggests that c‐Jun in Dendritic Cells (DC) contributes to psoriasis by controlling CCL2 and IL‐23 production, and further identifies the JNK/c‐Jun axis as a druggable target.
TLR7 (IMQ)‐induced skin inflammation was attenuated in mice lacking c‐Jun in DCs.
TLR7/JNK/c‐Jun signalling was required for CCL2 and IL‐23 transcription in human and murine DCs.
c‐Jun was co‐expressed with CCL2 and IL‐23 in type‐2/inflammatory DCs of human psoriatic skin.
Treatment with JNK inhibitor alleviated skin inflammation in mouse models of psoriasis.
Graphical Abstract
Based on genetically engineered mouse models (GEMMs) and human psoriasis biopsies, this study suggests that c‐Jun in Dendritic Cells (DC) contributes to psoriasis by controlling CCL2 and IL‐23 production, and further identifies the JNK/c‐Jun axis as a druggable target.
