Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses
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 a...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-04-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.00703/full |
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| author | 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 |
| author_facet | 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 |
| author_sort | Brianna N. Callahan |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-11T05:18:38Z |
| format | Article |
| id | doaj.art-2d9b0fbc80cd47fbafbd6ce2470522d9 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-11T05:18:38Z |
| publishDate | 2020-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-2d9b0fbc80cd47fbafbd6ce2470522d92022-12-22T01:19:45ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-04-011110.3389/fimmu.2020.00703525061Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell ResponsesBrianna N. Callahan0Ananth K. Kammala1Meesum Syed2Canchai Yang3Christopher J. Occhiuto4Rithvik Nellutla5Alena P. Chumanevich6Carole A. Oskeritzian7Rupali Das8Hariharan Subramanian9Department of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United StatesDepartment of Pathology, Microbiology, and Immunology, School of Medicine, University of South Carolina, Columbia, SC, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesDepartment of Physiology, Michigan State University, East Lansing, MI, United StatesMast 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.https://www.frontiersin.org/article/10.3389/fimmu.2020.00703/fullmast cellspseudo-allergic reactionsostholeMAS-related G-protein coupled receptor-X2MrgprB2 |
| spellingShingle | 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 Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses Frontiers in Immunology mast cells pseudo-allergic reactions osthole MAS-related G-protein coupled receptor-X2 MrgprB2 |
| title | Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses |
| title_full | Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses |
| title_fullStr | Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses |
| title_full_unstemmed | Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses |
| title_short | Osthole, a Natural Plant Derivative Inhibits MRGPRX2 Induced Mast Cell Responses |
| title_sort | osthole a natural plant derivative inhibits mrgprx2 induced mast cell responses |
| topic | mast cells pseudo-allergic reactions osthole MAS-related G-protein coupled receptor-X2 MrgprB2 |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.00703/full |
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