Activation of ryanodine-sensitive calcium store drives pseudo-allergic dermatitis via Mas-related G protein-coupled receptor X2 in mast cells.

Abstract

Mast cell (MC) activation is implicated in the pathogenesis of multiple immunodysregulatory skin disorders. Activation of an IgE-independent pseudo-allergic route has been recently found to be mainly mediated via Mas-Related G protein-coupled receptor X2 (MRGPRX2). Ryanodine receptor (RYR) regulates intracellular calcium liberation. Calcium mobilization is critical in the regulation of MC functional programs. However, the role of RYR in MRGPRX2-mediated pseudo-allergic skin reaction has not been fully addressed. To study the role of RYR in vivo, we established a murine skin pseudo-allergic reaction model. RYR inhibitor attenuated MRGPRX2 ligand substance P (SP)-induced vascular permeability and neutrophil recruitment. Then, we confirmed the role of RYR in an MC line (LAD2 cells) and primary human skin-derived MCs. In LAD2 cells, RYR inhibitor pretreatment dampened MC degranulation (detected by β-hexosaminidase retlease), calcium mobilization, IL-13, TNF-α, CCL-1, CCL-2 mRNA, and protein expression activated by MRGPRX2 ligands, namely, compound 48/80 (c48/80) and SP. Moreover, the inhibition effect of c48/80 by RYR inhibitor was verified in skin MCs. After the confirmation of RYR2 and RYR3 expression, the isoforms were silenced by siRNA-mediated knockdown. MRGPRX2-induced LAD2 cell exocytosis and cytokine generation were substantially inhibited by RYR3 knockdown, while RYR2 had less contribution. Collectively, our finding suggests that RYR activation contributes to MRGPRX2-triggered pseudo-allergic dermatitis, and provides a potential approach for MRGPRX2-mediated disorders.

• Authors: Zhao Wang, Xi Zhao, Hongmei Zhou, Delu Che, Xiaojie Du, Dan Ye, Weihui Zeng, Songmei Geng
• Journal: Frontiers in immunology (Front Immunol) Vol. 14 Pg. 1207249 ( 2023) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 37404822 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2023 Wang, Zhao, Zhou, Che, Du, Ye, Zeng and Geng.

Chemical References

• Calcium
• Ryanodine
• Ryanodine Receptor Calcium Release Channel
• Receptors, G-Protein-Coupled
• MRGPRX2 protein, human
• Nerve Tissue Proteins
• Receptors, Neuropeptide

Topics

• Humans
• Animals
• Mice
• Calcium (metabolism)
• Ryanodine (metabolism, pharmacology)
• Ryanodine Receptor Calcium Release Channel (genetics)
• Mast Cells (metabolism)
• Receptors, G-Protein-Coupled (metabolism)
• Dermatitis, Atopic (metabolism)
• Nerve Tissue Proteins (metabolism)
• Receptors, Neuropeptide (metabolism)