Mechanisms of Neuronal Differentiation and Notch Signaling as a Potential Therapeutic Target in Olfactory Dysfunction of Allergic Rhinitis

Chen Duan, Xinyi Ma, Fangying Liu, Xinyu Xie, Changhua Wu, Xiaojun Zhang, Ping Ye, Ye Yuan, Xin Feng Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology (Shandong University), Shandong Provincial Key Medical and Health Discipline of Qilu Hospital of Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Xin Feng, Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology (Shandong University), Shandong Provincial Key Medical and Health Discipline of Qilu Hospital of Shandong University, Jinan, People’s Republic of China, Email [email protected] Ye Yuan, Department of Otorhinolaryngology, Qilu Hospital of Shandong University, National Health Commission Key Laboratory of Otorhinolaryngology (Shandong University), Shandong Provincial Key Medical and Health Discipline of Qilu Hospital of Shandong University, Jinan, People’s Republic of China, Email [email protected]: Olfactory dysfunction (OD) in allergic rhinitis (AR) significantly diminishes quality of life, yet its pathophysiology remains unclear. The Notch signaling pathway is known to regulate olfactory epithelium proliferation and differentiation in murine models, but its role in AR with OD (AR+OD) is yet to be elucidated. This study aims to explore neuronal expression patterns and the involvement of Notch signaling in AR+OD.Patients and Methods: Symptom severity of 111 AR patients, 65 non-AR patients, and controls was evaluated according to the SNOT-22 criteria. Olfactory dysfunction in an AR mouse model was assessed via the Buried Food Pellet Test (BFPT). Immunofluorescence, H&E staining, ELISA, and PCR techniques were employed to detect inflammation and olfactory epithelium in AR+OD, AR without OD (AR-OD), and control groups. DAPT, a Notch signaling inhibitor, was administered to assess its therapeutic potential in OD of AR.Results: AR patients had higher sneezing, rhinorrhea, nasal itching, nasal congestion and olfactory scores, but no correlation was found between nasal congestion and olfactory dysfunction. Significant increases in the symptom scores, eosinophil infiltration, OVA-specific IgE levels and worse olfactory function were observed in the AR mice model compared to the Control group. In particular, AR+OD mice group exhibited thinner olfactory epithelium, increased immature neuron expression, decreased mature neurons, and upregulated Notch expression as compared to AR-OD group. DAPT treatment significantly enhanced olfactory mature neuron expression and improved OD of AR mice.Conclusion: Our research indicates that impaired differentiation of olfactory neurons may contribute to the underlying causes of olfactory dysfunction in AR. Additionally, inhibiting the Notch signaling pathway promotes the maturation of the olfactory epithelium and improves olfactory dysfunction in AR mice, offering potential therapeutic strategies for olfactory disorders in AR.Keywords: olfactory dysfunction, allergic rhinitis, Notch signaling pathway, neuron