Chronic interleukin‐13 expression in mouse olfactory mucosa results in regional aneuronal epithelium

Abstract

Background Olfactory dysfunction is highly associated with chronic rhinosinusitis with nasal polyps (CRSwNP), and the severity of loss has been linked with biomarkers of type 2 inflammation. The ability of dupilumab to rapidly improve the sense of smell prior to improvement in polyp size suggests a direct role of IL‐4/IL‐13 receptor signaling in the olfactory epithelium (OE). Methods We created a transgenic mouse model in which IL‐13 is inducibly expressed specifically within the OE. Gene expression analysis and immunohistology were utilized to characterize the effect of IL‐13 on the structure of the OE. Results After induction of olfactory IL‐13 expression, there is a time‐dependent loss of neurons from OE regions, accompanied by a modest inflammatory infiltrate. Horizontal basal cells undergo morphologic changes consistent with activation and demonstrate proliferation. Mucus production and increased expression of eotaxins is observed, with marked expression of Ym2 by sustentacular cells. Discussion Chronic IL‐13 exposure has several effects on the OE that are likely to affect function. The neuronal loss is in keeping with other models of allergic type 2 nasal inflammation. Future studies are needed to correlate cellular and molecular alterations in olfactory cell populations with findings in human CRSwNP, as well as to assess olfactory function in behavioral model systems.

Local cytokine levels associate with SNOT‐22 and UPSIT scores in chronic rhinosinusitis

“…These findings suggest that IL‐5 may contribute to both worsened symptomatology and smell loss independent of phenotype. IL‐13 has been correlated with the loss of olfactory neurons, inflammation, and mucus production in mouse models 6 . This study also supports the role of IL‐13 in olfactory dysfunction, perhaps at a neuronal level, and its association with increased disease severity 7 …”

New Concepts in Barrier Dysfunction in CRSwNP and Emerging Roles of Tezepelumab and Dupilumab

“…25,26 The rapid ability of dupilumab to improve sense of smell was investigated further in a transgenic mouse model with IL-13 specifically expressed within the olfactory epithelium. 27 Neuronal loss was seen associated with inflammatory infiltration by macrophages and increased expression of a mucin gene, MUC5AC, and eosinophil chemokines although eosinophil levels were unexpectedly low. The authors also note the potential for barrier dysfunction due to a possible reduction in airway epithelial cell diversity resulting from IL-13 exposure.…”

“…The authors also note the potential for barrier dysfunction due to a possible reduction in airway epithelial cell diversity resulting from IL-13 exposure. 27,28 Decreased expression of tight-junction proteins in IL-13-treated epithelial cells has been described including deficits in occludin, ZO-1, and claudin-3 with resulting mucous over-secretion and ciliary loss. 29 Alteration of olfactory epithelial barrier function via IL-13 exposure could also potentially affect neuronal function.…”

Olfaction Now and in the Future in CRSwNP

“…40 Saraswathula et al also recently created a transgenic mouse model in which IL-13 is expressed specifically within the OE, which also resulted in time-dependent neuronal loss in the OE region, HBC activation, and modest inflammatory cell infiltration. 41 Studies on Th1-mediated inflammation, which can be seen in CRSsNP or viral infections, through chronic IFN-γ expression have shown diminished odorant responsiveness in mice despite the absence of inflammatory tissue damage. 42 Other animal models of OE inflammation using lipopolysaccharide (LPS), which results in a robust inflammatory response and triggers the production of both Th1 and Th2 inflammatory cytokines, 43 have shown increase of IFN-γ, TNF-α, IL-1β, IL-6, and IL-10 cytokines and increased immune cell infiltration within the OB.…”