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ADAM8 mediates eosinophil and neutrophil infiltration and tissue remodeling in chronic rhinosinusitis with nasal
Ting He1, Xiangdong Wang1, Qinqin Zhang1
1Department of Otolaryngology Head and Neck Surgery, Beijing TongRen Hospital, Capital Medical University, Beijing, China; Beijing Institute of Otolaryngology, Beijing Laboratory of Allergic Diseases, Beijing Municipal Education Commission, Beijing Key Laboratory of New Medicine and Diagnostic Technology Research for Nasal Disease, Beijing, China.
Background:
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.
Objective:
We aimed to elucidate the role of ADAM8 and its underlying mechanisms in CRSwNP pathogenesis.
Methods:
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.
Results:
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.
Conclusion:
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.
Insights
A Disintegrin and Metalloproteinase 8 (ADAM8) drives inflammation and tissue remodeling in chronic rhinosinusitis with nasal polyps (CRSwNP). Inhibiting ADAM8 offers a potential therapeutic strategy for CRSwNP.
Area of Science:
- Immunology
- Pathology
- Otolaryngology
Background:
- Chronic rhinosinusitis with nasal polyps (CRSwNP) is characterized by eosinophilic and neutrophilic inflammation and tissue remodeling.
- The role of A Disintegrin and Metalloproteinase 8 (ADAM8) in CRSwNP pathogenesis is not well understood.
Purpose of the Study:
- To investigate the role of ADAM8 in CRSwNP pathogenesis.
- To elucidate the mechanisms by which ADAM8 contributes to CRSwNP.
Main Methods:
- Analysis of human nasal tissues using bulk and single-cell RNA sequencing, and histology.
- In vitro assessment of eosinophil and neutrophil migration, adhesion, and transendothelial migration.
- In vivo studies using a murine CRSwNP model treated with an ADAM8 inhibitor.
Main Results:
- ADAM8 expression is significantly elevated in CRSwNP tissues and correlates with disease severity and inflammatory cell infiltration.
- ADAM8 inhibition reduced eosinophil and neutrophil migration and adhesion.
- ADAM8 overexpression in nasal epithelial cells promoted inflammation and matrix metalloproteinase expression; ADAM8 inhibition in a murine model reduced polyp formation and tissue remodeling.
Conclusions:
- ADAM8 is a critical mediator of inflammation and tissue remodeling in CRSwNP.
- Targeting ADAM8 presents a promising therapeutic approach for CRSwNP, potentially effective across various subtypes.
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