AMBR2 Restores Airway Epithelial Integrity in Chronic Rhinosinusitis With Nasal Polyps.

Purpose: A defective epithelial barrier has been demonstrated in chronic rhinosinusitis with nasal polyps (CRSwNP). Lactobacilli are shown to restore epithelial barrier defects in gastrointestinal disorders, but their effect on the airway epithelial barrier is unknown. In this study, hence, we evaluated whether the nasopharyngeal isolates AMBR2 and AMBR8 could restore nasal epithelial barrier integrity in CRSwNP.

Methods: trans-epithelial tissue resistance and fluorescein isothiocyanate-dextran 4 kDa (FD4) permeability of nasal mucosal explants were measured. The relative abundance of lactobacilli in the maxillary sinus of CRSwNP patients was analyzed by amplicon sequencing of the V4 region of the 16S rRNA gene. The effect of spray-dried AMBR2 and AMBR8 on epithelial integrity was investigated in primary nasal epithelial cells (pNECs) from healthy controls and patients with CRSwNP as well as in a murine model of interleukin (IL)-4 induced barrier dysfunction. The activation of Toll-like receptor 2 (TLR2) was explored by using polyclonal antibodies.

Results: Patients with CRSwNP had a defective epithelial barrier which positively correlated with the relative abundance of lactobacilli-specific amplicons in the maxillary sinus. AMBR2, but not AMBR8, increased the trans-epithelial electrical resistance (TEER) of pNECs from CRSwNP patients in a time-dependent manner. Treatment of epithelial cells with AMBR2 promoted the tight junction proteins occludin and zonula occludens-1 reorganization. Furthermore, AMBR2 prevented IL-4-induced nasal permeability and . Finally, the beneficial effect of AMBR2 on nasal epithelial cells was TLR2-dependent as blocking TLR2 receptors prevented the increase in TEER.

Conclusions: A defective epithelial barrier in CRSwNP may be associated with a decrease in relative abundance of lactobacilli-specific amplicons. AMBR2 would restore nasal epithelial integrity and can be a novel therapeutic strategy for CRSwNP.