S1PR3 modulates the hyper-proliferation of keratinocytes in psoriasis by activating STAT3 in PKA/Src dependent manner

Background: Abnormal lipid metabolism influences the occurrence and development of psoriasis. Moreover, persistent activation of STAT3 signaling pathway in epidemies contributes to psoriasis. However, the molecular mechanism of lipid metabolism and STAT3 activation is unclear. Methods: Imiquimod (IMQ)-induced mouse psoriasis-like model was established to access the potential treatment of FTY720. The function of SIP receptors 3 (S1PR3) was determined by S1PR3 siRNA in HaCaTs and S1pr3 knock out in mice. RNA-seq in HaCaTs was undertaken to explore the downstream target of S1PR3. ChIP assay was applied to explore the transcription factor on S1PR3 promoter. Findings: The upregulation of S1PR3 in the lesion from psoriasis patients and IMQ-induced mice was observed. Moreover, the pan-S1PR modulator FTY720 ameliorated the lesion in IMQ-induced mice, which was mediated by internalizing S1PR3. S1PR3 knocking downing both in vivo and in vitro significantly suppressed the hyper-proliferation of keratinocytes in a P-STAT3-dependent manner. We found that upregulated-S1PR3 expression maintained STAT3 activation in psoriasis through both short and long term. Namely, S1PR3 enhanced early STAT3 activation via promoting the binding of P-Src to gp130, and long STAT3 activation by reducing Src. Ultimately, Upregulated-S1PR3 was due to STAT3 binding to S1PR3 promoter in psoriatic skin.