Respiratory diseases, including bacterial pneumonia, viral infections and allergic asthma, are leading causes of hospitalization, yet current therapies often fall short. The lower airways are densely innervated by pain-transmitting sensory neurons (nociceptors) that arise from the nodose-jugular ganglia of the vagus nerve, with additional contributions from the spinal dorsal root ganglia. Converging evidence indicates that reciprocal neuroimmune signalling between lung-innervating sensory neurons and immune cells lies at the centre of pulmonary defence, inflammation and tissue repair. Among several immunomodulatory neuropeptides, calcitonin gene-related peptide (CGRP), released by activated TRPV1-positive nociceptors, has context-dependent functions. CGRP supports tissue protection and repair by shaping macrophage and neutrophil activation states, yet these same actions can exacerbate pathology during bacterial infection. In allergic asthma, pulmonary neuroendocrine cells act as early epithelial sentinels that amplify type 2 immunity and help to define state-dependent effects of CGRP as well as other neuropeptides, including vasoactive intestinal peptide (VIP), neuromedin U (NMU) and substance P (SP). An updated framework that accounts for phase-specific and context-specific neuromodulation could enable new therapeutic strategies, including targeted inhibition or modulation of defined pathways to preserve essential reflexes while meaningfully altering disease trajectories and outcomes. Incorporating the neural state and exposure history will be critical for developing disease-modifying therapies informed by pulmonary neuroimmunology.
Ehlers et al. (Thu,) studied this question.