Inhibition of Airway Epithelial CTSC Attenuates Type 2 Inflammation: Implications for Eosinophilic Chronic Rhinosinusitis with Nasal Polyps.

PURPOSE: Cathepsin C (CTSC) has been identified as a key pathogenic gene in chronic rhinosinusitis. This study aimed to investigate the specific function and subcellular localization of CTSC within the nasal mucosal epithelium. PATIENTS AND METHODS: A total of 34 patients with eosinophilic chronic rhinosinusitis with nasal polyps (eNP), 32 with non-eosinophilic chronic rhinosinusitis with nasal polyps (neNP), and 16 control subjects were enrolled. Airway epithelial morphology was examined by scanning electron microscopy. The expression, localization, and function of CTSC in epithelial cells were assessed using single-cell RNA sequencing (scRNA-seq), immunohistochemistry, quantitative real-time PCR, Western blot, and an siRNA-mediated knockdown approach in an IL-4/IL-13-stimulated 16HBE cell line model. RESULTS: scRNA-seq revealed that CTSC was primarily localized to goblet cells and basal cells within the nasal epithelium, with its expression significantly upregulated in eNP patients compared with those in control subjects and neNP. These findings were confirmed at both the RNA and protein levels in clinical tissue samples. CTSC mRNA expression showed a significant positive correlation with the expression of T-helper 2 cytokines, including IL-4 and IL-13. In vitro experiments demonstrated that CTSC expression was induced in 16HBE cells upon IL-4/IL-13 stimulation. siRNA-mediated knockdown of CTSC led to pronounced suppression of IL-4/IL-13-induced release of CCL26, IL-25, and TNF-α, underscoring its functional involvement in inflammatory responses. CONCLUSION: This study identifies CTSC as a novel regulator of type 2 inflammation like eNP. It is specifically upregulated in nasal epithelial goblet and basal cells, highlighting its potential as a therapeutic target for airway diseases.