A pulmonary innate lymphoid cell-driven serotonergic neuroimmune axis orchestrates airway hyperreactivity and cough...

Asthma is a heterogeneous disease characterized by airway hyperreactivity (AHR) and chronic cough, exacerbated by respiratory viruses or allergen exposure. Yet, the immune pathway-mediated serotonergic circuits underlying these responses remain poorly defined. Here, we identified a serotonergic neuroimmune axis in which pulmonary group 2 innate lymphoid cells (ILC2s) expressed tryptophan hydroxylase-1 (Tph1) and released serotonin via CCAAT/enhancer-binding protein beta (C/EBPβ)-dependent transcription following interleukin (IL)-33 stimulation. Tph1 deficiency in ILC2s and adoptive transfer experiments demonstrated that ILC2-derived serotonin amplified type 2 cytokine production via 5-hydroxytryptamine (5-HT)_2A-NF-κB activation, resulting in exacerbated AHR in respiratory syncytial virus-driven asthmatic models. Using engineered viral tools, we showed that ILC2-derived serotonin sensitized vagal sensory neurons through 5-HT_3A to promote cough hypersensitivity. Clinically, asthma patients exhibited elevated TPH1 and plasma serotonin levels, both of which correlated with type 2 cytokines. Together, these findings reveal that an ILC2-driven serotonergic circuit contributes to asthma pathophysiology and highlight serotonergic signaling as a therapeutic target.