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

Area of Science:

• Neuroimmunology
• Allergic Inflammation
• Rhinitis Pathogenesis

Background:

• Allergic rhinitis (AR) traditionally viewed as IgE-mediated, but this fails to explain persistent symptoms and treatment resistance.
• Neuro-immune interactions are increasingly recognized as crucial in AR pathogenesis.
• The Substance P (SP)-Mas-related G protein-coupled receptor X2 (MrgprX2) axis is a key mediator of IgE-independent inflammation.

Purpose of the Study:

• To integrate evidence into a unified neuro-immune framework for AR.
• To elucidate the role of the SP-MrgprX2 axis in AR pathogenesis.
• To propose mechanism-guided therapeutic strategies for refractory AR.

Main Methods:

• Review and integration of current scientific evidence on neuro-immune interactions in AR.
• Delineation of molecular mechanisms, signaling dynamics, and neuro-immune synapse organization of the SP-MrgprX2 axis.
• Discussion of crosstalk with broader inflammatory networks.

Main Results:

• The SP-MrgprX2 axis orchestrates inflammation initiation, amplification, and maintenance beyond IgE-dependent pathways.
• SP release activates MrgprX2 on mast cells, causing immediate, IgE-independent inflammation.
• Sustained activation leads to epithelial barrier disruption, neutrophil inflammation, and neuro-immune feedback loops promoting chronicity.

Conclusions:

• The SP-MrgprX2 axis is a critical link between neural activation and chronic inflammation in AR.
• This neuro-immune paradigm extends beyond IgE-mediated disease.
• Targeting the SP-MrgprX2 axis offers a foundation for precision management of refractory AR.