Salidroside alleviates imiquimod-induced psoriasis by inhibiting GSDMD-driven keratinocyte pyroptosis

Psoriasis is a common immune-related polygenic inflammatory skin disease. Salidroside (SAL) exerts anti-inflammatory and antioxidant effects and is used to treat skin diseases. However, the specific effects of SAL on psoriasis remain unclear. In this study, we aimed to investigate the efficacy of SAL for psoriasis treatment. Mice were treated with imiquimod (IMQ) to establish an in vivo psoriasis model. Histological analysis was conducted via hematoxylin and eosin staining. Cytokine release was determined via enzyme-linked immunosorbent assay. Additionally, mRNA levels were determined via reverse transcription-quantitative polymerase chain reaction. Protein expression was assessed via Western blotting. Gasdermin D (GSDMD) and Ki-67 expression levels were determined via immunohistochemistry. Caspase 1 and GSDMD expression levels were determined via immunofluorescence assay. Furthermore, macrophage function and keratinocyte pyroptosis were also analyzed via flow cytometry. Cell proliferation was determined using 5-ethynyl-2ʹdeoxyuridine assay. SAL alleviated IMQ-induced psoriasis. IMQ-mediated GSDMD-driven pyroptosis and keratinocyte hyperproliferation promoted M1 macrophage polarization. However, SAL treatment suppressed GSDMD expression, thereby inhibiting keratinocyte proliferation and pyroptosis and promoting M2 macrophage polarization. GSDMD deficiency further promoted the effects of SAL and suppressed psoriasis progression. Overall, our findings suggest that SAL exerts protective effects against psoriasis. Specifically, it exerts anti-inflammatory effects by regulating M2 macrophage polarization and inhibiting keratinocyte pyroptosis-driven proliferation induced by the immune microenvironment in psoriasis.