Int Immunopharmacol. 2026 Nov 2;191(Pt 1):117608. doi: 10.1016/j.intimp.2026.117608. Online ahead of print.
ABSTRACT
BACKGROUND: Generalized pustular psoriasis (GPP) is a severe autoinflammatory dermatosis driven by excessive IL-1/IL-36-neutrophil activation, with high disease burden and limited therapeutic options. The mechanisms underlying dysregulated neutrophil recruitment remain incompletely understood, and the lack of mechanistic models that capture key inflammatory features of GPP has limited mechanistic and therapeutic investigations of GPP. Cathepsin S (CTSS), a cysteine protease involved in IL-36γ activation and neutrophil recruitment, has not been investigated in GPP.
METHODS: CTSS expression in GPP lesions was analyzed using public bulk RNA sequencing, single-cell RNA sequencing, and patient samples. A mouse model capable of mimicking the neutrophilic inflammatory phenotype of GPP was established by combining topical imiquimod (IMQ) treatment with intradermal CTSS injection (IMQ + CTSS). Histological, transcriptomic, flow cytometry, ELISA, and cross-species bioinformatics analysis were performed to assess consistency between patients and mice. In vitro experiments and pharmacological inhibition with LY3000328 were used to investigate the functional role of CTSS.
RESULTS: CTSS was markedly elevated in GPP lesions, predominantly enriched in myeloid cells, and closely associated with neutrophil chemotaxis signatures. The IMQ + CTSS model captured key neutrophil-dominant clinical and histopathological features associated with GPP patients. Mechanistically, CTSS promoted keratinocyte-mediated neutrophil recruitment via NF-κB and p38/MAPK signaling pathways, upregulating IL-8 and ICAM-1 expression. Notably, pharmacological inhibition of CTSS with LY3000328 significantly attenuated neutrophilic inflammation in vivo and in vitro.
CONCLUSION: CTSS functions as a critical amplifier of neutrophilic inflammation in GPP and represents a potential therapeutic target. The IMQ + CTSS mouse model provides a mechanistic platform for investigating neutrophilic inflammation and evaluating potential therapeutic strategies targeting CTSS in GPP.
PMID:42971142 | DOI:10.1016/j.intimp.2026.117608