Neuroimmune circuits in respiratory pathophysiology: decoding molecular crosstalk for precision therapeutic targeting

The lung is a uniquely innervated barrier organ with dynamic neuroimmune interactions that critically regulate respiratory homeostasis. Despite the well-characterized gut-brain axis, pulmonary neuroimmune crosstalk remains an underexplored frontier. Emerging evidence implicates dysregulated neuron-immune dialogues as key drivers of respiratory pathologies, yet systematic dissection of their bidirectional mechanisms - from neurogenic immunomodulation to immune-mediated neural plasticity - is lacking.

This review establishes a hierarchical framework for pulmonary neuroimmune crosstalk. We first delineate the lung's specialized neuroimmune architecture, then synthesize cutting-edge evidence on neuron-immune dialogues across five major respiratory diseases: pulmonary infections, asthma, chronic obstructive pulmonary disease, pulmonary fibrosis and lung cancer. Notably, we identify feedback-regulated circuits encompassing intricate networks mediated by neurotransmitters (e.g. acetylcholine, norepinephrine), neuropeptides (e.g. substance P, CGRP), immune cells (e.g. ILC2s, macrophages, T cells), and cytokines (e.g. TNF-α, IL-1β).

Decoding key molecular targets within the neuroimmune axis provides novel strategies for predicting disease biomarkers (e.g. CGRP in early allergic inflammation) and refining therapeutic interventions (e.g. purposing anti-NGF biologics for neuropathic airway inflammation). This review specifically identifies promising targets - such as CGRP signalling in asthma and infections, and cholinergic pathways in COPD and lung cancer - for next-generation biologics and neuromodulatory therapies. This synthesis bridges neuroimmunology and clinical pulmonology, positioning neuroimmune crosstalk as a promising frontier in precision respiratory medicine and paving the way for an innovative therapeutic paradigm.