Exogenous analogues of substance P trigger pseudo-allergic reactions through activation of MRGPRX2

Abstract

Pseudo-allergic reactions are non-IgE-mediated immediate allergic reactions, and MRGPRX2 is a potential important target for pseudo-allergic reactions. Currently, numerous reports focus on the induction of pseudo-allergic reactions by small molecule drugs and endogenous peptides. However, insufficient attention has been paid to the pseudo-allergic reactions induced by exogenous peptides through MRGPRX2. Therefore, this study selected immunogenic peptide composition HL-9-5, which has a structure and properties similar to substance P, and its analogue HL-9-4. We conducted experiments through LAD2 cell β-hexosaminidase release, histamine release, cytokine release and MRGPRX2-HEK293 cell calcium mobilization assay in vitro, and mice paw swelling, serum histamine detection, hindpaw skin H&E and TB staining in vivo demonstrated that HL-9-4 and HL-9-5 can trigger pseudo-allergic reactions via MRGPRX2. Molecular docking further showed that SP, HL-9-4 and HL-9-5 can act on the same cavity in MRGPRX2, and ASP-174 was identified as the conserved site of interaction for all three compounds. Therefore, HL-9-4 and HL-9-5 are exogenous analogues of substance P that can induce pseudo-allergic reactions. This study laid the foundation for research on the mechanism of pseudo-allergic reactions induced by exogenous peptide compounds and was also of great significance for subsequent research on the interaction between various ligands and MRGPRX2 and for the development of peptide antagonists.