Dual blockade of IL-4 and IL-13 with dupilumab ameliorates sensorineural olfactory dysfunction in mice with eosinophilic sinonasal inflammation

Background: Dupilumab, an antibody that binds IL-4R alpha and inhibits IL-4 and IL-13 signals, has demonstrated efficacy in chronic rhinosinusitis with nasal polyps (CRSwNP) primarily characterized by type 2 inflammation. Current evidence suggests that the rate of improvement in olfactory dysfunction with dupilumab exceeds that of nasal polyp reduction, yet the underlying mechanism remains undisclosed. We hypothesize that dupilumab may initially ameliorate sensorineural olfactory dysfunction. Methodology: Male BALB/c mice were intranasally administered ovalbumin and Aspergillus protease for 12 weeks to induce eosinophilic sinonasal inflammation. Dupilumab treatment was also administered. The mice underwent histological assessment, olfactory behavioural test, and gene expression profiling to identify neuroinflammatory markers within the olfactory bulb. Results: Dupilumab treatment resulted in a reduction in the number of mucosal protruding lesions, as well as decreased infiltration of eosinophils and neutrophils, along with a decrease in olfactory sensory neuron injury. Furthermore, there was a downregulation in the mRNA expression related to microglia activation and neuroinflammation in the olfactory bulb. Conclusions: Dupilumab improves the sensorineural pattern of olfactory dysfunction in mice, potentially explaining why olfaction improves more rapidly than polyp reduction in patients with CRSwNP.