Roles of Interleukin-31 in Allergen-Driven Cough: Linking Protease-Activated Receptor-2 Activation and Vagal Ganglion Sensitization in a Dermatophagoides farinae-Induced Asthma Model.

BACKGROUND: Chronic cough, a distressing symptom of allergic asthma, possibly arises from the abnormal activation of airway-projecting sensory neurons. Levels of interleukin (IL)-31, a Th2 cytokine known for its neuronal effects in pruritus, are elevated in allergic disorders; however, its role in asthma-related cough remains unclear. Therefore, in this study, we aimed to determine the mechanism by which IL-31 influences cough-associated neuronal sensitization using a Dermatophagoides farinae (Derf)-induced asthma model. METHODS: Wild-type (WT) and Il31 knockout (KO) C57BL/6N mice were intranasally administered the Derf extract repeatedly. Lung tissues, bronchoalveolar lavage fluid, and hilar lymph nodes were analyzed via histology, flow cytometry, enzyme-linked immunosorbent assay, and quantitative polymerase chain reaction. Vagal and dorsal root ganglia were assessed via immunofluorescence assay and Ca2 + imaging. RESULTS: Protease-activated receptor (PAR)-2 activity was evaluated using the agonist SLIGRL-NH2. Derf upregulated Il31 levels in airway tissues. Notably, immune and histological parameters were comparable between WT and Il31 KO mice, indicating that IL-31 deficiency did not alter Th2-driven inflammation. In contrast, Derf-challenged WT mice exhibited increased Il31ra and F2rl1 (PAR-2) levels and PAR-2-positive neuron proportions in vagal ganglia, changes that were not observed in Il31 KO mice. Ca2 + imaging confirmed that PAR-2 responsiveness to SLIGRL-NH2 was enhanced only in WT asthma model mice. CONCLUSION: Overall, IL-31 modulated the neuronal, rather than immune, components of allergic asthma by enhancing the PAR-2-dependent excitability of vagal sensory neurons. These findings highlight the IL-31-PAR-2-vagal pathway as the potential mechanism of and therapeutic target for allergen-driven cough.