Paeoniflorin-6'-O-benzene sulfonate inhibits keratinocyte proliferation by restoring GRK2-JAK1 colocalization in mouse model of psoriasis.

Psoriasis is chronic inflammatory skin disease mediated by interactions between Th17 cells and keratinocytes that lead to excessive proliferation of keratinocytes, suggesting that anti-inflammatory and anti-proliferation molecules may be effective for the treatment. Paeoniflorin-6'-O-benesulfonic acid (CP-25), an esterified modifier of paeoniflorin, has exhibited potent anti-inflammatory and immunomodulatory properties in arthritis animal models and experimental Sjögren's syndrome. However, the involvement of CP-25 and its target G protein-coupled receptor kinase 2 (GRK2) in the development of psoriasis has not been explored. In this study, we found that GRK2 expression was abnormally elevated in the skin tissues of both psoriasis patients and imiquimod-induced psoriasis model mice. Furthermore, its inhibitor CP-25 reduced skin damage and systemic inflammation in model mice. Mechanically, CP-25 inhibited GRK2 translocation to the cytomembrane, thus decreasing colocalization of GRK2 and the βγ subunit of G protein (Gβγ), increasing colocalization of GRK2 with Janus kinase 1 (JAK1), and downregulating the JAK1-signal transduction and activator of transcription (STAT3) signaling pathway to reduce the hyperproliferation of keratinocytes, besides, CP-25-mediated inhibition of GRK2 translocation to the cytomembrane involved the GRK2 amino acid alanine 321 in keratinocytes. Our findings indicate that targeting GRK2 with CP-25 is a promising treatment for psoriasis.