Keratinocyte-specific STAT3 knockout attenuates imiquimod-induced psoriasiform phenotype in mice.

Signal transducer and activator of transcription 3 (STAT3) is critical in psoriasis, but keratinocyte-derived STAT3 remains unclear. This study investigated the effect of keratinocyte-specific STAT3 knockout on imiquimod (IMQ)-induced psoriasis-like dermatitis. Keratinocyte-specific STAT3 knockout (Conditional knockout, cKO) mice and littermate controls (LC) received daily topical 5% IMQ to induce psoriasis-like lesions. Lesion severity was assessed by PASI score, histopathology by H&E staining, and systemic inflammation by spleen index and serum chemokine C-X-C motif ligand (CXCL1), chemokine C-C motif ligand 20 (CCL20), and IL-22 levels (ELISA). Skin expression of inflammation, chemokine, and STAT3 pathway related factors was examined by immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (qRT-PCR), and western blot. In vitro, IL-17A-stimulated HaCaT cells were used with siRNA-mediated STAT3 knockdown; changes in STAT3 signaling and downstream factors were assessed by qRT-PCR and Western blot. In vivo, keratinocyte-specific STAT3 knockout significantly alleviated IMQ-induced skin lesions, reduced PASI score, improved barrier function, decreased spleen index, and lowered serum CXCL1, CCL20, and IL-22. It also suppressed IL-22, CXCL1, and CCL20 expression in skin and inhibited STAT3 activation. In vitro, IL-17A increased STAT3 phosphorylation, which was blocked by STAT3 knockdown, along with suppression of IL-22 and CXCL1 upregulation.