Isosalvianolic acid C-induced pseudo-allergic reactions via the mast cell specific receptor MRGPRX2.

Abstract

Pseudo-allergic reactions occurred in patients administered drugs for the first time, seriously threaten man's survival. Due to the frequent reports of pseudo-allergic reactions to Danshen injection, in our previous study, isosalvianolic acid C in Danshen injection was found to trigger off mast cell degranulation. However, the direct involvement and the mechanisms underlying pseudo-allergic reactions have not been elucidated. In this study, the pseudo-allergic reactions induced by isosalvianolic acid C were confirmed by an ear swelling assay, a hindpaw swelling and extravasation assay in vivo and mast cell degranulation assays in vitro. We also evaluated whether the pseudo-allergic effect is related to MRGPRX2, Isosalvianolic acid C induced Ca2+ mobilization was verified as MRGPRX2-related by Ca2+ imaging using mouse peritoneal mast cells (both wild-type and MrgprB2 knockout mice), MRGPRX2-expressing HEK293 and MrgprB2-expressing HEK293 cells. MRGPRX2-related pseudo-allergic reactions induced by Isosalvianolic acid C were further confirmed by MrgprB2 knockout mice and MRGPRX2 knockdown mast cells both exhibited reduced isosalvianolic acid C-induced pseudo-allergic effects. Furthermore, both the frontal analysis and molecular docking assays showed that isosalvianolic acid C has a considerable affinity with MRGPRX2. Based on the above experiments, the western blot analyses were conducted, the results indicated that isosalvianolic acid C induced Ca2+ mobilization and degranulation via the activation of PLC-γ and IP3R, and releasing chemokines via the activation of PLC-γ, PKC and P38. This study should alarm many clinicians that medicines containing isosalvianolic acid C might induce pseudo-allergic reactions, and it may provide guidance on safe dosage of these medicines in the process of production and use.

• Authors: Yuanyuan Lin, Jue Wang, Yajing Hou, Jia Fu, Di Wei, Qianqian Jia, Yanni Lv, Cheng Wang, Shengli Han, Langchong He
• Journal: International immunopharmacology (Int Immunopharmacol) Vol. 71 Pg. 22-31 (Jun 2019) ISSN: 1878-1705 [Electronic] Netherlands
• PMID: 30875538 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Alkenes
• Mrgprb2 protein, mouse
• Mrgprx2 protein, mouse
• Polyphenols
• RNA, Small Interfering
• Receptors, G-Protein-Coupled
• Phospholipase C gamma
• salvianolic acid C

Topics

• Alkenes (metabolism)
• Anaphylaxis (chemically induced, metabolism)
• Animals
• Calcium Signaling
• Cell Degranulation
• Disease Models, Animal
• HEK293 Cells
• Humans
• Mast Cells (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Molecular Docking Simulation
• Phospholipase C gamma (metabolism)
• Polyphenols (metabolism)
• RNA, Small Interfering (genetics)
• Receptors, G-Protein-Coupled (genetics, metabolism)
• Signal Transduction