This study investigated how pulmonary ILC2s drive airway hyperreactivity (AHR) and cough hypersensitivity in asthma via a serotonergic neuroimmune axis, using RSV-driven asthma mouse models, adoptive transfer, engineered viral tools, and clinical samples from asthma patients.
ILC2s expressing Tph1 released serotonin under IL-33 stimulation via C/EBPβ-dependent transcription; this serotonin amplified type 2 cytokine production through 5-HT2A–NF-κB signaling (worsening AHR) and sensitized vagal sensory neurons via 5-HT3A (promoting cough hypersensitivity). Clinically, asthma patients showed elevated TPH1 and plasma serotonin levels that correlated with type 2 cytokines.
Causal human data are associational only (correlation of TPH1 and plasma serotonin with type 2 cytokines); mouse models rely on RSV-driven asthma, which may not fully represent all asthma endotypes; translation of serotonergic targeting to clinical intervention was not tested.
Serotonergic signaling through ILC2-derived serotonin is a mechanistic driver of both AHR and cough hypersensitivity in asthma, making 5-HT2A and 5-HT3A receptors plausible therapeutic targets. Clinicians should watch for emerging trials targeting this pathway, particularly in patients with poorly controlled cough and type 2-high asthma.
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