Eosinophil-derived neurotoxin enhances airway remodeling in eosinophilic chronic rhinosinusitis and correlates with disease severity

Abstract

Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis (CRS) that is characterized by intractable nasal polyp formation. Eosinophil-derived neurotoxin (EDN) is an eosinophil granule protein that is closely related to allergic inflammation, but the pathological implications of EDN in ECRS remain unknown. In this study, we evaluated the function of EDN in ECRS pathogenesis and assessed its potential as a disease activity marker. Serum EDN levels were significantly higher in patients with ECRS than in those with other nasal and paranasal diseases, and were positively correlated with clinical disease activity. Production of EDN from isolated human eosinophils was induced by stimulation with IL-5 in vitro. Human nasal epithelial cells (HNEpCs) were stimulated with EDN, and the resultant changes in gene expression were detected by RNA sequencing. Pathway analysis revealed that the major canonical pathway affected by EDN stimulation was "regulation of the epithelial-mesenchymal transition (EMT) pathway;" the only gene in this pathway to be up-regulated was matrix metalloproteinase 9 (MMP9). Consistent with this, immunostaining analysis revealed intense staining of both EDN and MMP-9 in nasal polyps from patients with ECRS. In conclusion, our data demonstrate that serum EDN level is a useful marker for the evaluation of ECRS severity. Furthermore, EDN induces production of MMP-9 from the nasal epithelium, which may be involved in the pathogenesis of ECRS.

Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis

“…In addition, we have previously shown that eosinophil granule protein acts on nasal epithelial cells to enhance MMP-9 production. 31 Based on these findings, it is considered that epithelial cells are one of the main sources of MMP-9 in ECRS. Interestingly, the expression of membrane SEMA4D on eosinophils was downregulated in patients with ECRS, whereas downregulation of SEMA4D was not detected in other leukocytes, suggesting that the MMP-9-mediated shedding process of eosinophils is unique and specific.…”

Synergy of Interleukin (IL)-5 and IL-18 in eosinophil mediated pathogenesis of allergic diseases

“…Eosinophils in response to Staphylococcus aureus, release EDN [37]. EDN induces production of MMP-9 from the nasal epithelium and involves in the pathogenesis of chronic eosinophilic rhinosinusitis [38]. Eosinophil-derived neurotoxin correlated with the disease severity of AD and considered as a serum biomarker for disease severity in atopic dermatitis [39].…”

Eosinophil-derived neurotoxin: A biologically and analytically attractive asthma biomarker

“…Elevated levels of EDN have been observed in asthma patients, with higher levels being measured during asthma exacerbations compared to those with stable asthma [14]. Furthermore, sustained exposure to high levels of EDN may have detrimental effects on the surrounding tissues with EDN being linked to airway remodelling in eosinophilic chronic rhinosinusitis by inducing production of matrix metalloproteinase 9 [15]. This suggests that prolonged airway exposure to elevated levels of EDN may be a risk factor for the progression of disease pathology.…”