Paeoniflorin inhibits MRGPRX2‐mediated pseudo‐allergic reaction via calcium signaling pathway

Abstract

Mas-related G protein-coupled receptor-X2 (MRGPRX2) expressed on mast cells (MCs) has been shown to be a pivotal target for pseudo-allergic diseases. Therefore, MRGPRX2 might be a therapeutic target for allergic contact dermatitis, atopic dermatitis, and red man syndrome. Paeoniflorin (PF) was reported to have an antiinflammatory effect in neuroinflammation, enteritis, and so forth. In this study, we investigated the anti-pseudo-allergic effect of PF and the underlying molecular mechanisms. Our results showed that PF can suppress compound 48/80 (C48/80)-induced PCA and MCs degranulation in vivo, in a dose-dependent manner. Moreover, PF can reduce C48/80-induced calcium influx and suppress MC degranulation and chemokines release in vitro. PF can downregulate the phosphorylation levels of key kinases in PLCγ-regulated calcium influx and subsequent cytokine synthesis pathways. Our study revealed that PF could inhibit C48/80-induced allergic responses both in vivo and in vitro. As such, it may be regarded as a novel inhibitor for preventing MRGPRX2mediated allergic diseases.

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells

“…In addition, naturally occurring compounds such as isoliquiritigenin (a component of licorice), shikonin (a component of Lithospermum erythrorhizon), imperatorin (an active furocumarin in Angelica Dahurica radix ), and roxithromysin (a derivative of erythromycin) were shown to bind to MRGPRX2 in molecular docking studies and surface plasmon resonance (SPR) and inhibit C48/80 or SP-induced passive cutaneous anaphylaxis (PCA) in mice [ 50 , 142 , 143 , 144 ]. Paeoniflorin (a component of Paeonia Lactiflora ), quercetin (a plant flavonoid), and genistein (a non-steroidal polyphenol), which were found to bind MRGPRX2 only in the docking model, also suppressed C48/80-induced PCA in mice [ 145 , 146 , 147 ]. On the other hand, naturally occurring components such as piperine, isoliquiritigenin, and shikonin are also known to act on various enzymes [ 141 , 160 , 161 ].…”

Nutraceutical Aid for Allergies – Strategies for Down-Regulating Mast Cell Degranulation

“…84 Another agent with the potential for inhibiting both FcεRI and MRFPRX2 signaling in mast cells is paeoniflorin, a bioactive component in peony flower extracts; the mast cell stabilizing action of this agent has been demonstrated both in mast cell cultures and in rodent allergy models. [85][86][87][88] The direct molecular target of its action in this regard has yet to be defined.…”

Mas-related G protein–coupled receptor X2 and its activators in dermatologic allergies

“…For example, MRGPRX2 antagonists have recently been identified and have been able to completely inhibit the degranulation of human cord blood-derived MCs 197 and lessen C48/80-induced local allergic inflammation in mice. 198 Targeting of MRGPRX2 further enables aimed MC depletion as recently described 9 and may thus introduce new treatment options for patients with dermatologic allergies.…”