IL-17A Promotes Psoriasis-Associated Keratinocyte Proliferation through ACT1-Dependent Activation of YAP–AREG Axis

Psoriasis is a recurrent inflammatory skin disorder characterized by epidermal hyperplasia, which is primarily driven by IL-17A. The Hippo–YAP signaling pathway plays a vital role in cell survival and tissue growth, and its target gene, AREG, has been reported to promote the development of psoriasis. However, whether IL-17A promotes keratinocyte proliferation through regulating Hippo–YAP signaling has not been explored. In this study, we show that the YAP–AREG pathway is activated in human psoriatic skin and is suppressed by IL-17A antagonist secukinumab and that imiquimod and IL-17A administration activates the YAP–AREG axis in mice epidermis. In vitro studies using HaCaT and normal human epidermal keratinocyte cells suggest that IL-17A enhances AREG expression and keratinocyte proliferation by activating Hippo–YAP signaling. Mechanistically, IL-17A stimulates the recruitment of MST1 to ACT1 in keratinocytes, which leads to reduced MST1–LATS1 interaction and YAP dephosphorylation. Together, our findings reveal a previously unknown mechanism in which IL-17A promotes keratinocyte proliferation in psoriasis, namely through activating YAP–AREG signaling.