Small proline-rich protein 2A drives epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps via SAA2 upregulation.

BACKGROUND: Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) is a severe subtype of chronic rhinosinusitis characterized by eosinophilic inflammation, type 2 immune responses, and tissue remodeling in the sinonasal mucosa. OBJECTIVE: We sought to identify genes contributing to eCRSwNP pathogenesis and elucidate their roles in epithelial dysfunction and tissue remodeling. METHODS: Transcriptome sequencing was conducted on nasal tissues from patients with eCRSwNP, noneosinophilic CRSwNP (neCRSwNP), and healthy controls and from a CRSwNP mouse model with small proline-rich protein 2A knockout (Sprr2a(-/-)) mice. Epithelial-mesenchymal transition (EMT) was examined in the CRSwNP mouse model and air-liquid interface culture system with nasal epithelial cells. RESULTS: Transcriptomic analysis revealed that SPRR2A expression was significantly elevated in eCRSwNP nasal tissues compared with neCRSwNP and healthy controls. High SPRR2A expression correlated with increased eosinophil infiltration, epithelial thickness, and IL-13 levels. In the CRSwNP mouse model, Sprr2a(-/-) mice displayed reduced epithelial thickness, fewer nasal polyps, lower IL-4 and IL-13 levels, and attenuated EMT. In vitro, nasal epithelial cells from Sprr2a(-/-) mice demonstrated reduced EMT markers and preserved barrier integrity. Further transcriptomic analysis identified serum amyloid A3 (Saa3) as a downstream mediator of SPRR2A. Saa3 expression was reduced in Sprr2a(-/-) mice, whereas serum amyloid A2 (SAA2 [human]) was upregulated in eCRSwNP compared with neCRSwNP and healthy controls and positively correlated with SPRR2A levels. In air-liquid interface cultures, Saa3 induced EMT and barrier dysfunction and increased IL-6, thymic stromal lymphopoietin, IL-33, and TGF-β1 production. CONCLUSIONS: These findings suggest that SPRR2A promotes eosinophilic inflammation and tissue remodeling via SAA2, highlighting the SPRR2A-SAA2 axis as a potential therapeutic target in eCRSwNP.