A long-term mixed eosinophilic and neutrophilic chronic rhinosinusitis C57BL/6 mouse model with neuroinflammation, olfactory dysfunction and anxiety-like behaviors

Background

Chronic rhinosinusitis (CRS) is a heterogeneous condition characterized by persistent inflammation and high recurrence rates. The mixed granulocytic endotype, marked by increased eosinophils and neutrophils, is particularly refractory and prone to relapse.

Objective

This study aimed to evaluate the papain-induced mouse model for investigating the more refractory mixed granulocytic CRS endotype, characterized by elevated eosinophils and neutrophils.

Methods

Male C57BL/6 mice were intranasally administered papain for 11 days to induce CRS. Cytokine profiles, nasal tissue histology, olfactory bulb analysis, assessments of olfactory function, cognition, anxiety-like and depression-like behaviors were performed at 30, 60, and 90 days post-treatment.

Results

A long-term mixed eosinophilic and neutrophilic CRS model was successfully established, showing elevated IgE, IL-4, IL-5, IL-13, IL-33, TSLP, and TNF-α in nasal lavage fluid, alongside infiltration of eosinophils and neutrophils in both olfactory and respiratory regions. Chronic pathology included increased mast cells, goblet cells, basal cells, mucus hyperproduction, and epithelial damage, persisting up to 90 days, with partial improvement observed at the 60-day mark. Brain analysis revealed ongoing neuroinflammation, olfactory dysfunction, and anxiety-like behaviors in CRS mice, without signs of cognitive impairment or depression-like behaviors.

Conclusions

This study phenotypically delineated a long-term mixed eosinophilic and neutrophilic CRS mouse model, demonstrating sustained neuroinflammation, olfactory dysfunction, and anxiety-like behaviors following short-term papain exposure. These findings highlighted the role of mixed inflammation in CRS and provided a time-efficient platform for further exploration of its pathogenesis and mind-brain-body interactions.