Notch‐1 signaling activation sustains overexpression of interleukin 33 in the epithelium of nasal polyps

• Published in: Journal of cellular physiology 2019-04, Vol.234 (4), p.4582-4596
• Main Authors: Chiappara, G., Sciarrino, S., Di Sano, C., Gallina, S., Speciale, R., Lorusso, F., Di Vincenzo, S., D’Anna, C., Bruno, A., Gjomarkaj, M., Pace, E.
• Format: Article
• Language: English
• Subjects: Adult; Cell Line; Chronic Disease; chronic rhinosinusitis; Cyclic AMP response element-binding protein; Cyclic AMP Response Element-Binding Protein - metabolism; Cytokines; Epithelial cells; Epithelial Cells - immunology; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelium; Female; Flow cytometry; Homeostasis; Humans; IL‐33; Immunocytochemistry; Immunofluorescence; Immunohistochemistry; Interleukin-33 - metabolism; Interleukins; Jagged-1 Protein - metabolism; Male; Middle Aged; Mucosa; nasal epithelium; Nasal Mucosa - immunology; Nasal Mucosa - metabolism; Nasal Mucosa - pathology; nasal polyps; Nasal Polyps - immunology; Nasal Polyps - metabolism; Nasal Polyps - pathology; Notch1 protein; Notch‐1; Pathogenesis; Phosphorylation; Polyps; Receptor, Notch1 - metabolism; Rhinitis; Rhinitis, Allergic - immunology; Rhinitis, Allergic - metabolism; Rhinitis, Allergic - pathology; Rhinosinusitis; Signal Transduction; Signaling; Sinusitis; Sinusitis - immunology; Sinusitis - metabolism; Sinusitis - pathology; Stimulation; Transcription factors; Up-Regulation; Young Adult
• ISSN: 0021-9541; 1097-4652
• DOI: 10.1002/jcp.27237

Background Alterations in the nasal epithelial barrier homeostasis and increased interleukin 33 (IL‐33) expression contribute to the pathogenesis of chronic rhinosinusitis with nasal polyps (CRSwNP). Aims As Notch‐1 signaling is crucial in repair processes of mucosa, the current study assessed Notch‐1/Jagged‐1 signaling and IL‐33 in the epithelium of nasal polyps biopsies from allergic (A‐CRSwNP; n = 9) and not allergic (NA‐CRSwNP; n = 9) subjects by immunohistochemistry. We also assessed, in a model of nasal epithelial cells, the effects of stimulation of Notch‐1 with Jagged‐1 on the expression of IL‐33 (by flow cytometry, immunofluorescence, and immunocytochemistry), Jagged‐1 (by flow cytometry), and p‐CREB transcription factor (by western blot analysis). Results Ex vivo (a) in normal epithelium, the expression of Notch‐1 and IL‐33 were higher in NA‐CRSwNP than in A‐CRSwNP; (b) in metaplastic epithelium, the expression of Notch‐1, Jagged‐1, and IL‐33 were higher in NA‐CRSwNP than in A‐CRSwNP; (c) in hyperplastic epithelium, the expression of Notch‐1, Jagged‐1, and IL‐33 were higher in A‐CRSwNP than in NA‐CRSwNP; and (d) in basal epithelial cells, no differences were observed in the expression of Jagged‐1, IL‐33, and Notch‐1. The expression of Notch‐1 significantly correlated with the expression of IL‐33. In vitro, stimulation of Notch‐1 with Jagged‐1 induced the expression of (a) Jagged‐1; (b) IL‐33; and (c) p‐CREB transcription factor. The inhibitor of Notch‐1, DAPT, reduced all the effects of Jagged‐1 on nasal epithelial cells. Conclusions The data herein provided support, for the first time, a putative role of Notch‐1/Jagged‐1 signaling in the overexpression of IL‐33 in the epithelium of nasal polyps from patients with CRSwNP. The current study assessed for the first time Notch‐1, Jagged‐1, and interleukin 33 expression in the epithelium of CRSwNP from allergic and not allergic exsmoker subjects. The data demonstrated a role of Notch‐1/Jagged‐1 signaling in a positive feedback upregulating Jagged‐1 expression and in promoting proinflammatory responses inducing p‐CREB and IL‐33 expression in nasal epithelial cells.