Inhibition of CTSC contributes to psoriasis inflammation and keratinocyte hyperproliferation by NF-κB signaling...

It was found that mutations in the Cathepsin C (CTSC) gene are responsible for Papillon-Lefevre syndrome which has a characteristic clinical feature of palmoplantar hyperkeratosis and psoriasiform lesions. However, its function in psoriasis is unclear so far. This study aims to investigate the roles and mechanisms of CTSC in psoriasis. The expression of CTSC was investigated by the analysis of single cell RNA sequencing (scRNA-seq) data and skin lesions of psoriasis patients. The role of CTSC in psoriasis was analyzed in human immortalized keratinocytes (HaCaT) stimulated with different inflammatory factors and mice of imiquimod (IMQ)-induced psoriasiform dermatitis. We showed that the expression of CTSC was significantly increased in the analysis of scRNA-seq data, which was identified in skin lesions of psoriasis patients and IMQ-induced psoriasis-like mice, and primary human keratinocytes and HaCaT cells stimulated with a cocktail of cytokines. In the presence of inflammatory factors or IMQ, CTSC inhibitor and knockdown of CTSC using siRNA exhibited significantly increased keratinocytes proliferation and the levels of proinflammatory cytokines. In vitro and in vivo experiments further showed that inhibited CTSC in psoriasis could activate the pathway of nuclear factor-κB (NF-κB). This study firstly outlines that inhibition of CTSC can contribute to inflammation and keratinocyte hyperproliferation by NF-κB pathway in psoriasis. It may provide a new perspective on understanding of the pathogenesis of psoriasis.