Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses

Brianna N. Callahan, Ananth K. Kammala, Meesum Syed, Canchai Yang, Christopher J. Occhiuto, Rithvik Nellutla, Alena P. Chumanevich, Carole A. Oskeritzian, Rupali Das, Hariharan Subramanian

Research output: Contribution to journalArticlepeer-review

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 (Ca2+ mobilization and degranulation) and delayed events (chemokine/cytokine production) of mast cell activation via MRGPRX2 in vitro. Osthole also inhibits MrgprB2- (mouse ortholog of human MRGPRX2) dependent inflammation in in vivo 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.

Original languageEnglish (US)
Article number703
JournalFrontiers in immunology
Volume11
DOIs
StatePublished - Apr 24 2020
Externally publishedYes

Keywords

  • MAS-related G-protein coupled receptor-X2
  • MrgprB2
  • mast cells
  • osthole
  • pseudo-allergic reactions

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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