Interplay between keratinocyte STATI and STAT3 signaling controls skin inflammation and T-cell development in a mouse model of psoriasis

Abstract Psoriasis is an autoimmune skin disease affecting 2–3% of the population that is driven by IL-17 responses. Although STAT3 promotes the development of IL-17-producing T cells, STAT3 overexpression in keratinocytes is sufficient to induce psoriasiform dermatitis in mice. To study the role of STAT3 in keratinocytes versus T cells in psoriasis, the imiquimod mouse model of psoriasiform dermatitis was performed on mice with specific deletion of STAT3 in either keratinocytes (K5-creERT2×STAT3fl/fl [K5-STAT3]) or T-cells (Lck-cre×STAT3fl/fl [Lck-STAT3]). Unexpectedly, K5-STAT3 mice but not Lck-STAT3 mice had reduced skin inflammation and inflammatory cell influx compared to wt mice, suggesting that STAT3 signaling in keratinocytes rather than T cells was more important determinant for mediating the skin inflammation. K5-STAT3 mice also had increased IFN-γ+ T cells but less IL-17+ T-cells compared to wt mice, indicating that loss of STAT3 signaling in keratinocytes dampened inflammation by inhibiting IL-17 responses while promoting IFN-γ responses. Since interferon/STAT1 signaling responses can be inhibited by STAT3, we hypothesized that loss of STAT3 signaling in keratinocytes would lead to enhanced interferon/STAT1-signaling and responses. Consistent with this possibility, histologic sections from the inflamed skin of K5-STAT3 mice had increased epidermal STAT1 phosphorylation and increased mRNA expression of interferon-regulated chemokines CXCL10 and CXCL11 compared with wt mice. Taken together, these findings indicate that keratinocytes can regulate T cell responses in the skin and STAT3 signaling in keratinocytes could represent a therapeutic target in psoriasis.