MrgprX2 regulates mast cell degranulation through PI3K/AKT and PLCγ signaling in pseudo-allergic reactions
https://doi.org/10.1016/j.intimp.2021.108389
Fan Zhang ab, Fang Hong ab, Lu Wang ac, Renjie Fu a, Jin Qi a, Boyang Yuab
aJiangsu Key Laboratory for TCM Evaluation and Translational Research, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 21198, China
bResearch Center for Traceability and Standardization of TCMs, China Pharmaceutical University, Nanjing 211198, China
cNanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, China
Received 10 August 2021, Revised 27 October 2021, Accepted 9 November 2021, Available online 15 December 2021, Version of Record 15 December 2021.
Highlights
- •MrgprX2 is a key receptor for pseudo-allergic reactions.
- •PI3K/AKT signaling pathway and PLCγ are important downstream of MrgprX2.
- •Inhibiting PI3K/AKT signaling pathway and PLCγ remarkable weakened pseudo-allergic reactions both in vivo and in vitro.
Abstract
The G protein-coupled receptor MrgprX2 in mast cells is known to be a crucial receptor for pseudo-allergic reactions. MrgprX2 activation leads to elevated intracellular calcium levels and mast cell degranulation, but the underlying mechanism remains to be elucidated. Herein, we investigated the role of the phosphatidylinositol 3 kinase (PI3K)/serum-threonine kinase (AKT) signaling pathway and phospholipase C gamma (PLCγ) in mast cell degranulation mediated by MrgprX2 in LAD2 human-derived mast cells. The results showed that phosphorylated AKT (p-AKT) and PLCγ up-regulation were accompanied by an increase in intracellular calcium following activation of MrgprX2 by Compound 48/80, an inducer of mast cell degranulation. In contrast, p-AKT and PLCγ were down-regulated and intracellular calcium levels decreased after MrgprX2 knockdown. Mast cell degranulation was clearly suppressed; however, inhibiting PI3Kand PLCγ phosphorylation did not influence MrgprX2 expression. The increase in calcium concentration was suppressed and mast cell degranulation was weakened. Furthermore, by inhibiting PI3K and PLCγ phosphorylation in animals, the allergic symptoms caused by C48/80 were obviously reduced. We deduced that during the mast cell degranulation observed in pseudoallergic reactions, MrgprX2 regulated intracellular calcium levels via the PI3K/AKT and PLCγ pathways.
Keywords
Pseudo-allergic reactions, Mast cell, MRGPRX2, PI3K/AKT, PLCγ
