Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses.
Callahan. Brianna N BN; Kammala. Ananth K AK; Syed. Meesum M; Yang. Canchai C; Occhiuto. Christopher J CJ; Nellutla. Rithvik R; Chumanevich. Alena P AP; Oskeritzian. Carole A CA; Das. Rupali R; Subramanian. Hariharan H
Key Findings
- Osthole blocks early calcium signaling and degranulation of mast cells activated via MRGPRX2
- It also suppresses later cytokine/chemokine production and reduces MRGPRX2 surface and intracellular levels
- In mouse models, osthole lessens MRGPRX2‑driven pseudo‑allergic inflammation without directly competing with ligands
Practical Outcomes
- Osthole could be explored as a natural supplement to reduce mast‑cell‑driven allergic or pseudo‑allergic symptoms, especially for people sensitive to LL‑37 or similar triggers. However, because the evidence is limited to cell cultures and mice, users should wait for human safety and dosage studies before adding it to a regimen.
Summary
The study shows that osthole, a natural compound from plants, can calm down mast cells that cause allergic‑type reactions when they’re triggered by things like the antimicrobial peptide LL‑37, substance P, or certain drugs. It works by lowering the cells' calcium spikes, preventing them from releasing inflammatory chemicals, and even reducing the amount of the receptor (MRGPRX2) on the cell surface. These effects were seen in lab dishes and in mice, suggesting osthole might help prevent pseudo‑allergic reactions, but human data are still missing.
Abstract
Mast cells are tissue-resident innate immune cells known for their prominent role in mediating allergic reactions. MAS-related G-protein coupled receptor-X2 (MRGPRX2) is a promiscuous G-protein coupled receptor (GPCR) expressed on mast cells that is activated by several ligands that share cationic and amphipathic properties. Interestingly, MRGPRX2 ligands include certain FDA-approved drugs, antimicrobial peptides, and neuropeptides. Consequently, this receptor has been implicated in causing mast cell-dependent pseudo-allergic reactions to these drugs and chronic inflammation associated with asthma, urticaria and rosacea in humans. In the current study we examined the role of osthole, a natural plant coumarin, in regulating mast cell responses when activated by the MRGPRX2 ligands, including compound 48/80, the neuropeptide substance P, and the cathelicidin LL-37. We demonstrate that osthole attenuates both the early (Ca<sup>2+</sup> mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 <i>in vitro</i>. Osthole also inhibits MrgprB2- (mouse ortholog of human MRGPRX2) dependent inflammation in <i>in vivo</i> mouse models of pseudo-allergy. Molecular docking analysis suggests that osthole does not compete with the MRGPRX2 ligands for interaction with the receptor, but rather regulates MRGPRX2 activation via allosteric modifications. Furthermore, flow cytometry and confocal microscopy experiments reveal that osthole reduces both surface and intracellular expression levels of MRGPRX2 in mast cells. Collectively, our data demonstrate that osthole inhibits MRGPRX2/MrgprB2-induced mast cell responses and provides a rationale for the use of this natural compound as a safer alternative treatment for pseudo-allergic reactions in humans.
Study Information
pubmed
2020
2020-04-24T00:00:00.000Z
10.3389/fimmu.2020.00703
61
66