Neuromedin U Activation of Group 2 Innate Lymphocytes Exacerbates Local Inflammation of Nasal Mucosa in Allergic Rhinitis

PURPOSE: Allergic rhinitis (AR) is no longer considered an immune dysregulation disorder but rather a neuroimmune disorder regulated by neuronal signals. However, the mechanisms underlying these effects remain unclear. Therefore, we evaluated whether the local nasal mucosa is regulated by neuroimmune signals during nasal allergic reactions. METHODS: We identified genes that were differentially expressed between patients with AR and healthy controls using GSE46171 gene chip data. Expression levels of neuromedin U (NMU), NMU receptor 1 (NMUR1), and group 2 innate lymphoid cells (ILC2s) in the nasal mucosa were determined the impacts of NMU on patients with AR were assessed. An AR animal model was established to observe the effects of local NMU intervention on local and systemic ILC2s in the nasal cavity. RESULTS: We identified 1,137 differentially expressed genes and focused on the neuropeptide NMU. NMU was widely distributed in the lamina propria of the nasal mucosa of patients with AR. NMUR1 was expressed at high levels in the lamina propria, basal layer, and glandular epithelium. Local ILC2 expression in the nasal mucosa of the AR group was elevated and positively correlated with NMU and NMUR1 expression. Using the AR model, we found that NMU significantly enhanced both local and systemic inflammatory responses in ovalbumin-sensitized mice and promoted activation of ILC2s to release additional type 2 inflammatory cytokines. However, this effect was blocked by an extracellular signal-regulated kinase (ERK) pathway inhibitor, indicating that NMU activates ILC2s via the ERK pathway, contributing to AR pathogenesis. CONCLUSIONS: During nasal allergic reactions, local NMU increases significantly in the nasal cavity, activating ILC2s via the ERK pathway to release type 2 cytokines, thereby participating in or exacerbating the onset of AR. These findings lay the groundwork for exploration of diverse factors that contribute to AR and suggest new approaches to prevention and treatment.