P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice
Abstract Pseudoallergies caused by drugs make disease treatment difficult. Mas-relate G protein-coupled receptor X2 (MRGPRX2), which is specifically expressed in mast cells (MCs), has been implicated in pseudoallergies. High concentrations of therapeutic agents are typically required to stimulate MR...
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| Format: | Article |
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Nature Portfolio
2022-11-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-022-21667-6 |
| _version_ | 1811223483599814656 |
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| author | Kazuki Yoshida Shota Tanihara Yuki Miyashita Kosuke Obayashi Masa-aki Ito Kimiko Yamamoto Toshiyashu Imai Isao Matsuoka |
| author_facet | Kazuki Yoshida Shota Tanihara Yuki Miyashita Kosuke Obayashi Masa-aki Ito Kimiko Yamamoto Toshiyashu Imai Isao Matsuoka |
| author_sort | Kazuki Yoshida |
| collection | DOAJ |
| description | Abstract Pseudoallergies caused by drugs make disease treatment difficult. Mas-relate G protein-coupled receptor X2 (MRGPRX2), which is specifically expressed in mast cells (MCs), has been implicated in pseudoallergies. High concentrations of therapeutic agents are typically required to stimulate MRGPRX2. Although regulatory mechanisms may enhance this response, the factors involved in this regulation are not well-understood. In this study, the effects of extracellular ATP on MC activation induced by MrgprB2, the mouse ortholog of human MRGPRX2, were examined in mouse peritoneal MCs (PMCs). ATP alone induced minimal PMC degranulation but markedly enhanced degranulation induced by the MrgprB2 agonist compound 48/80 (CP48/80), substance P, PAMP-12, and vancomycin. ATP promoted CP48/80-induced increase in intracellular Ca2+ in PMCs. This enhancement effect of ATP was absent in PMCs prepared from P2X4 receptor (P2X4R)-deficient mice and inhibited by the PI3K inhibitor wortmannin. In addition, P2X4R deficiency reduced the skin-specific and systemic anaphylactic responses to CP48/80 in vivo. In MC-deficient Kit W-sh/W-sh mice, reconstitution with MCs obtained from wild-type mice led to a more severe anaphylactic response to CP48/80 compared to that from P2X4R-deficient mice. P2X4R-mediated effect may be involved in MrgprB2-mediated MC activation in vivo and is a potential target for alleviating pseudoallergic reactions. |
| first_indexed | 2024-04-12T08:33:37Z |
| format | Article |
| id | doaj.art-007a9a11f612412bb966363624ffe02c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-12T08:33:37Z |
| publishDate | 2022-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-007a9a11f612412bb966363624ffe02c2022-12-22T03:40:04ZengNature PortfolioScientific Reports2045-23222022-11-011211910.1038/s41598-022-21667-6P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in miceKazuki Yoshida0Shota Tanihara1Yuki Miyashita2Kosuke Obayashi3Masa-aki Ito4Kimiko Yamamoto5Toshiyashu Imai6Isao Matsuoka7Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareLaboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareDepartment of Biomedical Engineering, Graduate School of Medicine, The University of TokyoDiscovery Research Laboratories, Nippon Chemiphar Co., Ltd.Laboratory of Pharmacology, Faculty of Pharmacy, Takasaki University of Health and WelfareAbstract Pseudoallergies caused by drugs make disease treatment difficult. Mas-relate G protein-coupled receptor X2 (MRGPRX2), which is specifically expressed in mast cells (MCs), has been implicated in pseudoallergies. High concentrations of therapeutic agents are typically required to stimulate MRGPRX2. Although regulatory mechanisms may enhance this response, the factors involved in this regulation are not well-understood. In this study, the effects of extracellular ATP on MC activation induced by MrgprB2, the mouse ortholog of human MRGPRX2, were examined in mouse peritoneal MCs (PMCs). ATP alone induced minimal PMC degranulation but markedly enhanced degranulation induced by the MrgprB2 agonist compound 48/80 (CP48/80), substance P, PAMP-12, and vancomycin. ATP promoted CP48/80-induced increase in intracellular Ca2+ in PMCs. This enhancement effect of ATP was absent in PMCs prepared from P2X4 receptor (P2X4R)-deficient mice and inhibited by the PI3K inhibitor wortmannin. In addition, P2X4R deficiency reduced the skin-specific and systemic anaphylactic responses to CP48/80 in vivo. In MC-deficient Kit W-sh/W-sh mice, reconstitution with MCs obtained from wild-type mice led to a more severe anaphylactic response to CP48/80 compared to that from P2X4R-deficient mice. P2X4R-mediated effect may be involved in MrgprB2-mediated MC activation in vivo and is a potential target for alleviating pseudoallergic reactions.https://doi.org/10.1038/s41598-022-21667-6 |
| spellingShingle | Kazuki Yoshida Shota Tanihara Yuki Miyashita Kosuke Obayashi Masa-aki Ito Kimiko Yamamoto Toshiyashu Imai Isao Matsuoka P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice Scientific Reports |
| title | P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice |
| title_full | P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice |
| title_fullStr | P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice |
| title_full_unstemmed | P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice |
| title_short | P2X4 receptor stimulation enhances MrgprB2-mediated mast cell activation and pseudoallergic reactions in mice |
| title_sort | p2x4 receptor stimulation enhances mrgprb2 mediated mast cell activation and pseudoallergic reactions in mice |
| url | https://doi.org/10.1038/s41598-022-21667-6 |
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