RIPK3 promotes S100A8/A9 production in keratinocytes as a key pathway in psoriasis progression

Psoriasis is a chronic inflammatory skin disease, and the interplay between the IL-17 pathway and the damage-associated molecular patterns (DAMPs) S100A8/A9 creates a feedback loop that sustains inflammation. However, the regulatory mechanism of this loop is not fully understood.

To investigate the role of Receptor-Interacting Protein Kinase 3 (RIPK3) in regulating S100A8/A9 in the progression of psoriasis.

We analyzed RIPK3 expression in the epidermis of human psoriatic skin lesions. To assess the function of RIPK3 in vivo, we utilized keratinocyte-specific RIPK3-deficient mice in both imiquimod-induced and IL-23-induced models of psoriasiform dermatitis. In vitro, we performed RIPK3 knockdown in human keratinocytes stimulated with IL-17A. We further examined the underlying signaling pathways and performed rescue experiments using recombinant S100A8/A9.

RIPK3 expression was elevated in psoriatic skin lesions and correlated positively with disease severity. In mouse models, keratinocyte-specific deficiency of RIPK3 ameliorated skin damage and inhibited the production of S100A8/A9 in the epidermis. In vitro, RIPK3 knockdown inhibited IL-17A-induced proliferation and suppressed S100A8/A9 production in human keratinocytes. Mechanistically, STAT1 is required for RIPK3-enhanced S100A8/A9 production. Furthermore, the administration of recombinant S100A8/A9 restored the psoriatic phenotype in keratinocyte-specific RIPK3-deficient mice.

Our findings unveil a critical role for RIPK3 in driving psoriasis by modulating STAT1-associated signaling to amplify S100A8/A9 production in keratinocytes. These results highlight RIPK3 as a potential therapeutic target for the treatment of psoriasis.