Calcitonin gene-related peptide as a neuroimmune amplifier in allergic rhinitis: from disease worsening to targeted drug intervention.

Allergic rhinitis (AR) has long been viewed as a type 2 inflammatory disease driven by IgE, mast cells and eosinophils. However, this classic model does not explain all clinical variation. Some patients continue to experience nasal congestion, nasal hyperreactivity and symptoms triggered by non-specific stimuli despite antihistamines, intranasal corticosteroids or allergen immunotherapy. Calcitonin gene-related peptide (CGRP), a potent vasodilatory neuropeptide mainly released by trigeminal sensory nerves, provides a plausible link between sensory activation, vascular responses, epithelial barrier function and immune-cell regulation. Here, we propose CGRP as a candidate neuroimmune amplifier in AR, while emphasizing that this concept remains a testable framework rather than an established causal pathway. The strongest AR-relevant evidence supports CGRP-mediated nasal vasodilation and obstruction. Evidence that CGRP directly amplifies human type 2 inflammation is more indirect and is partly extrapolated from airway, skin, gut and in vitro immune models. Current evidence mainly comes from nasal allergen challenge, neuropeptide measurement in nasal secretions, nasal mucosal tissue studies and intranasal CGRP challenge. CGRP biology is also context-dependent. In some settings, CGRP can suppress dendritic-cell activation or reshape T-cell and ILC2 responses, indicating that it should not be regarded as uniformly pro-inflammatory. Based on the success of CGRP-targeted drugs in migraine, local CGRP receptor antagonists may be useful tools to test a neurogenic AR endotype. These agents demonstrate pharmacological targetability, but not therapeutic efficacy in AR. Future studies should combine standardized nasal-secretion CGRP measurements with congestion-dominant symptoms, nasal hyperreactivity and objective airflow endpoints to determine whether a reproducible CGRP-high AR subgroup exists.