Palbociclib blocks neutrophilic phosphatidylinositol 3-kinase activity to alleviate psoriasiform dermatitis

Background and Purpose: Neutrophilic inflammation is a critical pathogenic factor in psoriasis. The therapeutic applicability of palbociclib, a cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor clinically used to treat cancer, in the treatment of neutrophil-associated psoriasis remains undefined. In this study, we evaluated the therapeutic potential and pharmacological effect of palbociclib on neutrophil-associated psoriasiform dermatitis. Experimental Approach: The anti-inflammatory effects of palbociclib were determined in activated human neutrophils. The therapeutic feasibility of palbociclib in psoriasis was demonstrated in a mouse model of imiquimod-induced psoriasiform dermatitis. The in vitro enzymatic assays and in silico analyses were used to identify the underlying pharmacological mechanisms. Key Results: This study found that palbociclib inhibited neutrophilic inflammation, including superoxide anion generation, reactive oxygen species (ROS) formation, elastase degranulation and chemotactic responses. The mechanistic studies identified that the anti-inflammatory effects of palbociclib involved the targeting of phosphatidylinositol 3-kinase (PI3K) but not CDK4/6 in human neutrophils. Palbociclib preferentially targeted the p110δ catalytic subunit of PI3K and thereby blocked signalling via the PI3K/protein kinase B (Akt) pathway. Furthermore, topical application of palbociclib significantly ameliorated imiquimod-induced psoriasiform dermatitis in mice, including psoriatic symptoms, neutrophil infiltration, Akt activation and cytokine up-regulation. Conclusions and Implications: This is the first study to demonstrate that palbociclib can potentially be used to treat neutrophil-associated psoriasiform dermatitis through the targeting of neutrophilic PI3K activity. Our findings prompt further research to explore the potential of palbociclib and PI3K in psoriasis and other inflammatory diseases.