The SP-MrgprX2 Axis in Allergic Rhinitis: a Neuro-immune Paradigm Beyond IgE-mediated Inflammation

Allergic rhinitis (AR) is traditionally defined as an IgE-mediated hypersensitivity disorder; however, this paradigm fails to explain the clinical heterogeneity observed in patients with persistent symptoms and poor therapeutic responsiveness. Emerging evidence indicates that neuro-immune interactions constitute a critical, yet underappreciated, layer of AR pathogenesis. Substance P (SP)-Mas-related G protein-coupled receptor X2 (MrgprX2) axis has recently been recognized as a central mediator of IgE-independent inflammation. Upon sensory neuron activation, SP is rapidly released and directly activates MrgprX2 on mast cells, initiating immediate inflammatory responses independent of FcεRI signaling. This pathway further drives epithelial barrier disruption and neutrophil-dominant inflammation, while sustained activation establishes neuro-immune positive feedback loops and central sensitization along the nose-brain axis, ultimately promoting chronicity and therapeutic refractoriness. Here, we integrate current evidence into a unified neuro-immune framework in which the SP-MrgprX2 axis orchestrates inflammation initiation, amplification, and maintenance beyond the classical IgE-dependent pathway. We further delineate its molecular recognition, signaling dynamics, and neuro-immune synapse organization, and discuss its crosstalk with broader inflammatory networks. On this basis, we propose mechanism-guided therapeutic strategies targeting distinct regulatory layers of this axis. Collectively, this review positions the SP-MrgprX2 axis as a key mechanistic bridge linking neural activation to chronic inflammation, advancing a neuro-immune paradigm that extends beyond IgE-mediated disease and providing a conceptual foundation for precision management of refractory AR.