Increased LOXL2 facilitates tissue remodeling in eosinophilic chronic rhinosinusitis with nasal polyps

Objective: Eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP) involves extensive tissue remodeling, but its underlying mechanisms remain unclear. This study aimed to identify key regulatory proteins contributing to this process.

Methods: Proteomic analysis was conducted on nasal tissues from 8 eCRSwNP patients, 8 non-eosinophilic CRSwNP (neCRSwNP) patients, and 8 healthy controls. Differentially expressed proteins (DEPs) were selected based on the top 50 overlapping DEPs from both comparison groups. Selected candidates were validated using Western blotting, immunofluorescence, and qRT-PCR in an independent cohort. Correlations with eosinophil infiltration and remodeling markers were assessed. Human nasal epithelial cells (HNECs) were used to explore functional mechanisms in vitro.

Result: Proteomic profiling revealed a distinct protein expression signature in the eCRSwNP group compared to both neCRSwNP and control groups. By intersecting the top 50 DEPs from both comparisons, 4 candidate proteins were identified, among which lysyl oxidase-like protein 2 (LOXL2) exhibited the most prominent upregulation. Validation in an independent cohort confirmed significantly elevated LOXL2 expression in eCRSwNP, predominantly localized to the nasal epithelial region (P < 0.001). LOXL2 mRNA levels were strongly correlated with eosinophil infiltration in nasal tissues (r = 0.349, P = 0.006), and ROC curve analysis supported its high diagnostic utility for eCRSwNP (AUC = 0.746, P = 0.001). Furthermore, the expression of EMT markers including vimentin, α-smooth muscle actin (α-SMA), and N-Cadherin was markedly increased in eCRSwNP tissues (all P < 0.01) and positively associated with LOXL2 expression (all P < 0.05). In vitro, stimulation of HNECs with recombinant LOXL2 induced TGF-β1 and EMT marker expression, while co-treatment with the TGF-β1/Smad signaling inhibitor LY364947 significantly attenuated these effects and inhibited SMAD2/3 phosphorylation.

Conclusion: Our findings revealed a disease-specific protein profile in eCRSwNP, characterized by selective upregulation of LOXL2 in the nasal epithelium and strong association with eosinophilic inflammation. Functional studies suggest that LOXL2 promotes EMT and may drive tissue remodeling in eCRSwNP via the TGF-β1/Smad signaling pathway.

Eosinophilic chronic rhinosinusitis with nasal polyps; Lysyl oxidase-like protein 2; Proteomics; Smad pathway; Tissue remodeling.