Dysregulated glia and periglomerular cells in the olfactory bulb and altered lipocalins in the olfactory epithelium underlie olfactory dysfunction in a murine model of eosinophilic chronic rhinosinusitis.

Abstract

Background: Eosinophilic chronic rhinosinusitis (ECRS) is a chronic inflammatory disease. It is characterized by type 2 inflammation and olfactory dysfunction. Although olfactory dysfunction in patients with ECRS may have sensorineural and central components, the underlying mechanism remains to be elucidated. We aimed to investigate changes in the olfactory bulb (OB) and olfactory epithelium (OE) associated with sinonasal type 2 inflammation, using a murine model of ECRS.

Methods: We developed a murine model of ECRS based on the topical application of calcipotriol and ovalbumin for 14 days and subsequent daily intranasal challenge with ovalbumin for 5 days. Histopathological analyses were performed to assess glial cells and periglomerular cells (PGCs) in the OB. Bulk RNA sequencing was performed to determine the impact of sinonasal type 2 inflammation on the OB and OE. Differentially expressed genes were identified using a false discovery rate < 0.05 (Benjamini-Hochberg adjustment). For molecules exhibiting marked fluctuations at the gene expression level, the protein expression was evaluated using enzyme-linked immunosorbent assay (ELISA).

Results: In the ECRS group, a significant increase was noted in the number of microglia/macrophages and astrocytes in the OB. In addition, the number of tyrosine hydroxylase-positive PGCs was significantly reduced in the OB of mice with ECRS. Bulk RNA sequencing analysis revealed a significant decrease in the gene expression levels of the lipocalin family in both the OB and OE. Subsequent ELISA confirmed a significant reduction in the protein levels of lipocalin 4 and major urinary protein 5 in the OE; conversely, lipocalin 3 levels in the OE were significantly increased. No significant differences were observed in the protein expression levels of these molecules within the OB.

Conclusion: Sinonasal type 2 inflammation causes various changes in the olfactory system. These changes may be involved in the pathogenesis of sensorineural and central olfactory dysfunction in ECRS.