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

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ABSTRACT 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 Ca 2 + imaging. Results Protease‐activated receptor (PAR)‐2 activity was evaluated using the agonist SLIGRL‐NH 2 . 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. Ca 2 + imaging confirmed that PAR‐2 responsiveness to SLIGRL‐NH 2 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.

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