Exosomes mediate interepithelial transfer of functional P-glycoprotein in chronic rhinosinusitis with nasal polyps

• Published in: The Laryngoscope Vol. 127; no. 9; p. E295
• Main Authors: Nocera, Angela L, Miyake, Marcel M, Seifert, Philip, Han, Xue, Bleier, Benjamin S
• Format: Journal Article
• Language: English
• Published: United States 01.09.2017
• Subjects: Adult; Aged; ATP-Binding Cassette, Sub-Family B, Member 1 - physiology; Case-Control Studies; Cell Communication; Chronic Disease; Enzyme-Linked Immunosorbent Assay; Epithelial Cells - physiology; Exosomes - physiology; Female; Humans; Male; Middle Aged; Nasal Mucosa - cytology; Nasal Polyps - metabolism; Rhinitis - metabolism; Sinusitis - metabolism; Young Adult; P-glycoprotein; rhinosome; epithelium; sinonasal mucus; Chronic rhinosinusitis with nasal polyps; exosome
• ISSN: 1531-4995
• DOI: 10.1002/lary.26614

P-glycoprotein (P-gp) drives type-2 helper T-cell inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) through unknown posttranslational mechanisms of overexpression. A recent randomized clinical trial demonstrated that inhibition of P-gp was as effective as oral steroids and biologics in treating CRSwNP. Exosomes are 30- to 150-nm vesicles capable of intercellular membrane protein transfer. The aims of this study were 1) to determine whether CRSwNP mucus exosomes are enriched with P-gp, and 2) whether exosomal P-gp can be functionally transferred to autologous epithelial cells as a putative mechanism for the proinflammatory overexpression of P-gp in CRSwNP. Institutional review board-approved study in CRSwNP and control patients (n = 10 per group). P-gp content of purified mucus exosomes was characterized by transmission electron microscopy and enzyme-linked immunosorbent assay. Epithelial transfer of exosomal P-gp was determined by time-lapse fluorescent microscopy and calcein acetoxymethylester functional P-gp assay. CD63+/P-gp+ exosomes were detected in both groups. P-gp was significantly enriched in CRSwNP exosomes relative to control (median 198.5; interquartile range 123.6-270.5 vs. 74.4; 41.3-95.0 pcg P-gp/10 exosomes, P = 0.002). Exosomes were absorbed by epithelial cells within 10 minutes, resulting in a significant increase in P-gp activity in CRSwNP patients relative to control (P = 0.006). Here we demonstrate the presence and P-gp enrichment of mucus-derived exosomes, or rhinosomes, in CRSwNP. These rhinosomes are capable of rapid intercellular transfer of P-gp, leading to increased P-gp function within recipient cells. This represents a novel mechanism for maintaining P-gp overexpression in CRSwNP, and more generally for interepithelial transfer of other proteins between mucosal epithelial cells. NA. Laryngoscope, 127:E295-E300, 2017.