Tumour necrosis factor alpha and interleukin-5 inhibit olfactory regeneration via apoptosis of olfactory sphere cells in mice models of allergic rhinitis

Background Olfactory dysfunction is frequently experienced by patients with allergic rhinitis. It is thought to result from structural and functional changes occurring in the olfactory mucosa caused by inflammation. However, the current understanding of the pathophysiology of olfactory dysfunction in allergic rhinitis remains unclear. Objective To investigate the mechanism by which the olfactory neural cells are damaged in allergic rhinitis. Methods Olfactory sphere cells (OSCs) were established after dissociation and serial cultures of cells from the mouse olfactory mucosa. Viability and proliferation of OSCs were compared between control and allergic rhinitis mice models, and olfactory stem cell markers were analysed in vivo. To elucidate which cytokines have an inhibitory effect on OSCs, viability and apoptotic markers of OSCs were investigated. Results Olfactory sphere cells were successfully isolated from the olfactory mucosa of mice, and these cells expressed markers of neural stem cells. To investigate the neural differentiation, we performed the immunocytochemical staining and found significantly elevated expressions of Tuji1, GFAP and O4 on OSCs. On the comparison of the characteristics of OSCs between control and allergic rhinitis model, we detected significantly fewer neurospheres, reduced clonogenic capacity and decreased expression of olfactory neural stem cell markers in allergic rhinitis model. When OSCs were treated with several major allergic cytokines were treated on OSCs, only TNF-alpha showed an inhibitory effect on OSCs. Interestingly, IL-5 had an inhibitory effect on the viability of OSCs in combination with TNF-alpha, whereas IL-5 alone does not have an effect. Moreover, TNF-alpha combined with IL-5 significantly increased the apoptotic expression, compared with TNF-alpha or IL-5 alone. Additionally, allergic rhinitis mice models showed the increased apoptotic expression. Conclusion and Clinical Relevance Allergic rhinitis mice models showed lower expression of OSCs, and TNF-alpha combined with IL-5 had an apoptotic effect on OSCs. Therefore, these cytokines may be therapeutic targets for olfactory dysfunction in patients with allergic rhinitis.