Departmental Papers (Dental)
Document Type
Journal Article
Date of this Version
1-20-2022
Publication Source
Frontiers in Immunology
Volume
12
DOI
10.3389/fimmu.2021.803335
Abstract
Mast cells (MCs) are tissue resident immune cells that play important roles in the pathogenesis of allergic disorders. These responses are mediated via the cross-linking of cell surface high affinity IgE receptor (FcϵRI) by antigen resulting in calcium (Ca2+) mobilization, followed by degranulation and release of proinflammatory mediators. In addition to FcϵRI, cutaneous MCs express Mas-related G protein-coupled receptor X2 (MRGPRX2; mouse ortholog MrgprB2). Activation of MRGPRX2/B2 by the neuropeptide substance P (SP) is implicated in neurogenic inflammation, chronic urticaria, mastocytosis and atopic dermatitis. Although Ca2+ entry is required for MRGPRX2/B2-mediated MC responses, the possibility that calcium release-activated calcium (CRAC/Orai) channels participate in these responses has not been tested. Lentiviral shRNA-mediated silencing of Orai1, Orai2 or Orai3 in a human MC line (LAD2 cells) resulted in partial inhibition of SP-induced Ca2+ mobilization, degranulation and cytokine/chemokine generation (TNF-α, IL-8, and CCL-3). Synta66, which blocks homo and hetero-dimerization of Orai channels, caused a more robust inhibition of SP-induced responses than knockdown of individual Orai channels. Synta66 also blocked SP-induced extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt phosphorylation and abrogated cytokine/chemokine production. It also inhibited SP-induced Ca2+ mobilization and degranulation in primary human skin MCs and mouse peritoneal MCs. Furthermore, Synta66 attenuated both SP-induced cutaneous vascular permeability and leukocyte recruitment in mouse peritoneum. These findings demonstrate that Orai channels contribute to MRGPRX2/B2-mediated MC activation and suggest that their inhibition could provide a novel approach for the modulation of SP-induced MC/MRGPRX2-mediated disorders. Copyright © 2022 Chaki, Alkanfari, Roy, Amponnawarat, Hui, Oskeritzian and Ali.
Keywords
Calcium release-activated calcium (CRAC), Mas-related G protein-coupled receptor B2 (MrgprB2), Mas-related G protein-coupled receptor X2 (MRGPRX2), Mast cells, Orai, Substance P
Recommended Citation
Chaki, S., Alkanfari, I., Roy, S., Amponnawarat, A., Hui, Y., Oskeritzian, C. A., & Ali, H. (2022). Inhibition of Orai Channel Function Regulates Mas-Related G Protein-Coupled Receptor-Mediated Responses in Mast Cells. Frontiers in Immunology, 12 http://dx.doi.org/10.3389/fimmu.2021.803335
Date Posted: 10 February 2023
This document has been peer reviewed.