MRGPRX2: Mast cell-specific marker

•  Gene Information: MRGPRX2 (Mas-related G-protein coupled receptor member X2) is a protein-coding gene located on chromosome 11p15.1. MRGPRX2 belongs to the G-protein coupled receptor (GPCR) family and functions as a pattern and cationic ligand recognition receptor.
•  Protein Expression: MRGPRX2 is predominantly expressed on tissue-resident mast cells (especially in the skin and mucosa). Acting as a receptor for endogenous cationic peptides (such as Substance P and LL-37), it drives IgE-independent mast cell degranulation.
•  Signaling Pathway: Upon binding to its cationic ligands, activation of downstream phospholipase C (PLC) and PI3K/AKT pathways leads to inositol trisphosphate (IP₃) production and rapid intracellular calcium (Ca²⁺ )influx. This triggers rapid mast cell degranulation, releasing preformed mediators like histamine and tryptase, along with pro-inflammatory cytokines, driving neurogenic inflammation and pseudoallergic reactions. 
• Therapeutic Inhibition: As a key receptor driving IgE-independent pseudoallergy, drug-induced hypersensitivity, and neurogenic inflammation, small-molecule antagonists or monoclonal antibodies targeting MRGPRX2 represent promising therapeutic avenues for conditions such as chronic urticaria, atopic dermatitis, and chronic neuropathic itch or pain.

MRGPRX2

•  The coding region and 3’UTR of mouse Mrgprb2 gene that encode extracellular domain, transmembrane domain and cytoplasmic region are replaced by human MRGPRX2 counterparts in B-hMRGPRX2 mice plus.

MRGPRX2 expression analysis in homozygous MRGPRX2 humanized mice by flow cytometry. Peritoneal lavage fluid cells were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hMRGPRX2 mice plus (H/H), and analyzed by flow cytometry with anti-human MRGPRX2 antibody (BioLegend, 359004). hMRGPRX2 was detectable in peritoneal lavage fluid mast cells in homozygous B-hMRGPRX2 mice plus, but not in wild-type mice.

MRGPRX2 expression analysis in homozygous MRGPRX2 humanized mice by flow cytometry.
Splenocytes were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hMRGPRX2 mice plus (H/H), and analyzed by flow cytometry with anti-human MRGPRX2 antibody (BioLegend, 359004). Human MRGPRX2 was not detectable on T cells, B cells, NK cells, DCs, monocytes, macrophages, and neutrophils of spleen in C57BL/6JNifdc mice and homozygous B-hMRGPRX2 mice plus.

Human MRGPRX2 expression analysis in homozygous MRGPRX2 humanized mice by flow cytometry.
Blood cells were collected from wild-type C57BL/6JNifdc mice (+/+) and homozygous B-hMRGPRX2 mice plus (H/H), and analyzed by flow cytometry with anti-human MRGPRX2 antibody (BioLegend, 359004). Human MRGPRX2 was not detectable on T cells, B cells, NK cells, DCs, monocytes, macrophages, and neutrophils of blood in C57BL/6JNifdc mice and homozygous B-hMRGPRX2 mice plus.

Effects of MRGPRX2 antagonist-1 on Cortistatin-14 induced systemic anaphylaxis-like reaction in MRGPRX2 humanized mice.
B-hMRGPRX2 mice plus (H/H) were challenged with Cortistatin-14 on day 0. MrgprX2 antagonist-1 (5 mpk, commercially purchased) was injected 4 h before challenge on day 0. Body temperature was recorded from 0 to 90 minutes after the challenge of 1 mg/kg Cortistatin-14. MrgprX2 antagonist-1 produced an increasing trend in the Cortistatin-14 induced systemic anaphylaxis-like reaction model and showed an inhibitory effect on the decrease in body temperature in B-hMRGPRX2 mice plus.