IL-17A disrupts the nasal mucosal epithelial barrier in patients with chronic rhinosinusitis by activating the ERK/STAT3 pathway

Abstract

Background: The mucosal epithelial barrier, the first line of immune defense, is vulnerable to allergens, pathogens, and inflammatory cytokines, contributing to CRS development. Our previous studies found high interleukin-17A(IL-17A) expression correlated with CRS severity and low glucocorticoid efficacy. The role of IL-17A in disrupting the nasal mucosal epithelial barrier leading to CRS remains unclear. We aimed to investigate how IL-17A promoting epithelial barrier damage and identify new treatment targets for CRS.

Methodology: Nasal tissue samples from 36 CRSwNP, 34 CRSsNP, and 39 controls were examined for the expression of IL-17A and tight junction (TJ) proteins using qRT-PCR, immunohistochemistry and immunofluorescence. The integrity of TJs and signaling pathways activation were observed using western blot, immunofluorescence, TEER and FITCâ€"FD4, transmission electron microscopy before and after IL-17A stimulation in human primary nasal epithelial cells (hNECs). Concurrently, studies were also conducted in an CRS mouse model induced by anti-IL-17A neutralizing antibody administration.

Results: TJs expression in the nasal mucosa of CRS patients was lower than in controls. IL-17A stimulation reduced TJs expression and TEER while increasing hNECs permeability. Inhibition of the (ERK/STAT3) pathway reversed the downregulation of TJs and the disruption of the epithelial barrier induced by IL-17A stimulation. In the CRS mouse model, anti-IL-17A antibody treatment rescued the nasal mucosal epithelial barrier.

Conclusions: IL-17A disrupts the nasal mucosal epithelial barrier by activating the ERK/STAT3 pathway in patients with CRS.