Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction

Research output: Contribution to journal › Journal article › Research › peer-review

Standard

Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction. / Tang, Xiao; Rönnberg, Elin; Säfholm, Jesper; Thulasingam, Madhuranayaki; Trauelsen, Mette; Schwartz, Thue W.; Wheelock, Craig E.; Dahlén, Sven Erik; Nilsson, Gunnar; Haeggström, Jesper Z.

In: Allergy: European Journal of Allergy and Clinical Immunology, Vol. 77, No. 9, 2022, p. 2677-2687.

Research output: Contribution to journal › Journal article › Research › peer-review

Harvard

Tang, X, Rönnberg, E, Säfholm, J, Thulasingam, M, Trauelsen, M, Schwartz, TW, Wheelock, CE, Dahlén, SE, Nilsson, G & Haeggström, JZ 2022, 'Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction', Allergy: European Journal of Allergy and Clinical Immunology, vol. 77, no. 9, pp. 2677-2687. https://doi.org/10.1111/all.15245

APA

Tang, X., Rönnberg, E., Säfholm, J., Thulasingam, M., Trauelsen, M., Schwartz, T. W., Wheelock, C. E., Dahlén, S. E., Nilsson, G., & Haeggström, J. Z. (2022). Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction. Allergy: European Journal of Allergy and Clinical Immunology, 77(9), 2677-2687. https://doi.org/10.1111/all.15245

Vancouver

Tang X, Rönnberg E, Säfholm J, Thulasingam M, Trauelsen M, Schwartz TW et al. Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction. Allergy: European Journal of Allergy and Clinical Immunology. 2022;77(9):2677-2687. https://doi.org/10.1111/all.15245

Author

Tang, Xiao ; Rönnberg, Elin ; Säfholm, Jesper ; Thulasingam, Madhuranayaki ; Trauelsen, Mette ; Schwartz, Thue W. ; Wheelock, Craig E. ; Dahlén, Sven Erik ; Nilsson, Gunnar ; Haeggström, Jesper Z. / Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction. In: Allergy: European Journal of Allergy and Clinical Immunology. 2022 ; Vol. 77, No. 9. pp. 2677-2687.

Bibtex

@article{a53bfd9b7e3b41a283246f48814869d2,
title = "Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction",
abstract = "Background: SUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated. Methods: Cord blood-derived mast cells and human mast cell line LAD-2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell-dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti-IgE, respectively. Results: SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non-metabolite agonist cis-epoxysuccinate, renders mast cells hypersensitive to IgE-dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate-potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal-regulated kinase. Both succinate and cis-epoxysuccinate dose-dependently potentiated antigen-induced contraction in a mast cell-dependent guinea pig airway model, associated with increased generation of cysteinyl-leukotrienes and histamine in trachea. Similarly, cis-epoxysuccinate aggravated IgE-receptor-induced contraction of human bronchi, which was blocked by SUCNR1 antagonism. Conclusion: SUCNR1 amplifies IgE-receptor-induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell-dependent inflammation.",
keywords = "allergic bronchoconstriction, eicosanoid, mast cell hyper-reactivity, succinate, SUCNR1",
author = "Xiao Tang and Elin R{\"o}nnberg and Jesper S{\"a}fholm and Madhuranayaki Thulasingam and Mette Trauelsen and Schwartz, {Thue W.} and Wheelock, {Craig E.} and Dahl{\'e}n, {Sven Erik} and Gunnar Nilsson and Haeggstr{\"o}m, {Jesper Z.}",
note = "Publisher Copyright: {\textcopyright} 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.",
year = "2022",
doi = "10.1111/all.15245",
language = "English",
volume = "77",
pages = "2677--2687",
journal = "Allergy: European Journal of Allergy and Clinical Immunology",
issn = "0105-4538",
publisher = "Wiley Online",
number = "9",

}

RIS

TY - JOUR

T1 - Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction

AU - Tang, Xiao

AU - Rönnberg, Elin

AU - Säfholm, Jesper

AU - Thulasingam, Madhuranayaki

AU - Trauelsen, Mette

AU - Schwartz, Thue W.

AU - Wheelock, Craig E.

AU - Dahlén, Sven Erik

AU - Nilsson, Gunnar

AU - Haeggström, Jesper Z.

N1 - Publisher Copyright: © 2022 The Authors. Allergy published by European Academy of Allergy and Clinical Immunology and John Wiley & Sons Ltd.

PY - 2022

Y1 - 2022

N2 - Background: SUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated. Methods: Cord blood-derived mast cells and human mast cell line LAD-2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell-dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti-IgE, respectively. Results: SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non-metabolite agonist cis-epoxysuccinate, renders mast cells hypersensitive to IgE-dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate-potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal-regulated kinase. Both succinate and cis-epoxysuccinate dose-dependently potentiated antigen-induced contraction in a mast cell-dependent guinea pig airway model, associated with increased generation of cysteinyl-leukotrienes and histamine in trachea. Similarly, cis-epoxysuccinate aggravated IgE-receptor-induced contraction of human bronchi, which was blocked by SUCNR1 antagonism. Conclusion: SUCNR1 amplifies IgE-receptor-induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell-dependent inflammation.

AB - Background: SUCNR1 is a sensor of extracellular succinate, a Krebs cycle intermediate generated in excess during oxidative stress and has been linked to metabolic regulation and inflammation. While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated. Methods: Cord blood-derived mast cells and human mast cell line LAD-2 challenged by SUCNR1 ligands were analyzed for the activation and mediator release. Effects on mast cell-dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti-IgE, respectively. Results: SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non-metabolite agonist cis-epoxysuccinate, renders mast cells hypersensitive to IgE-dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate-potentiated mast cell reactivity was attenuated by SUCNR1 knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal-regulated kinase. Both succinate and cis-epoxysuccinate dose-dependently potentiated antigen-induced contraction in a mast cell-dependent guinea pig airway model, associated with increased generation of cysteinyl-leukotrienes and histamine in trachea. Similarly, cis-epoxysuccinate aggravated IgE-receptor-induced contraction of human bronchi, which was blocked by SUCNR1 antagonism. Conclusion: SUCNR1 amplifies IgE-receptor-induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell-dependent inflammation.

KW - allergic bronchoconstriction

KW - eicosanoid

KW - mast cell hyper-reactivity

KW - succinate

KW - SUCNR1

U2 - 10.1111/all.15245

DO - 10.1111/all.15245

M3 - Journal article

C2 - 35122266

AN - SCOPUS:85124530445

VL - 77

SP - 2677

EP - 2687

JO - Allergy: European Journal of Allergy and Clinical Immunology

JF - Allergy: European Journal of Allergy and Clinical Immunology

SN - 0105-4538

IS - 9

ER -

ID: 298645817