Background: Dupilumab, which binds to interleukin-4 receptor alpha (IL-4Rα) and inhibits signaling of both IL-4 and IL-13, rapidly improves sense of smell in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) via unknown mechanisms. The current study aimed to investigate the effects of IL-4 and IL-13 in smell function in mice.
Methods: Calcium uptake was measured in primary murine olfactory sensory neurons (OSN) after acute challenge with IL-4 and/or IL-13. Sense of smell in mice was assessed at baseline and after 5 consecutive days of intranasal administration of IL-4 (10 µg) and/or IL-13 (10 µg) by time to discover hidden food. IL-4Rα antibody (dupilumab surrogate) was injected intraperitoneally. After treatments, the olfactory epithelium was dissected and subjected to RNA extraction for transcriptomic profiling and protein extraction for proteomic analysis.
Results: IL-4 and IL-13 increased calcium uptake in OSN. Interestingly, intranasal administration of IL-4, but not IL-13, induced anosmia. In transcriptome analysis, only IL-4 upregulated genes involved in olfactory/calcium signaling, neuronal regeneration, and immune response, and downregulated genes encoding olfactory receptors. Proteomic analysis demonstrated an effect of IL-4, but not IL-13, on inflammatory cell recruitment to the olfactory epithelium and showed activation of neuroinflammation pathways. Finally, IL-4Rα blockade restored the basal level of gene and protein expression, and the sense of smell.
Conclusions: Our data show IL-4, but not IL-13, elicits loss of smell in mice and support the hypothesis that the therapeutic effects of dupilumab in restoring smell function in patients with CRSwNP may be mediated predominantly through IL-4 signaling.
