ADAM8 mediates eosinophil and neutrophil infiltration and tissue remodeling in chronic rhinosinusitis with nasal polyps.

Abstract

Eosinophilic and neutrophilic inflammation, along with tissue remodeling, are key pathogenic features in chronic rhinosinusitis with nasal polyps (CRSwNP). While ADAM8 (a disintegrin and metalloproteinase 8) is implicated in inflammation and remodeling in various contexts, its specific role in CRSwNP remains unclear. We aimed to elucidate the role of ADAM8 and its underlying mechanisms in CRSwNP pathogenesis. Bulk RNA sequencing, single-cell RNA sequencing reanalysis, and histologic analysis were performed on human nasal tissues. Eosinophil and neutrophil migration, transendothelial migration, and adhesion were assessed in vitro.ADAM8 was overexpressed in a human nasal epithelial cell (HNEC) line (HNEpC) via transfection. Primary HNECs were stimulated with CRSwNP-related factors. In vivo, a murine CRSwNP model was treated with an ADAM8 inhibitor. ADAM8 expression was significantly elevated in both eosinophilic and noneosinophilic CRSwNP and was abundantly expressed by multiple inflammatory cells and epithelial cells. This elevation strongly correlates with inflammatory cell infiltration, tissue remodeling, and disease severity. ADAM8 inhibition reduced the migration, transendothelial migration, and adhesion to endothelial cells of both eosinophils and neutrophils. ADAM8 overexpression in HNEpCs activated inflammation pathways and upregulated the expression of matrix metalloproteinases (MMPs), including MMP2, MMP10, and MMP24. IL-4, IL-13, TGF-β1, and hypoxia upregulated ADAM8 in HNECs. In the murine CRSwNP model, ADAM8 inhibition reduced nasal polyp formation, eosinophil and neutrophil infiltration, and tissue remodeling. ADAM8 functions as a critical mediator of inflammatory cell infiltration and tissue remodeling in CRSwNP. Targeting ADAM8 represents a promising therapeutic strategy potentially applicable across different CRSwNP subtypes.