琥珀酸受体1的激活促进人类肥大细胞反应性和过敏性支气管收缩
2022/02/28
摘要
背景：SUCNR1是细胞外琥珀酸盐的传感器，琥珀酸盐是一种在氧化应激过程中过量产生的克雷布斯循环中间体，与代谢调节和炎症有关。
目的：虽然肥大细胞表达SUCNR1，但其在肥大细胞反应性和过敏性疾病(如哮喘)中的作用仍有待阐明。
方法：分析SUCNR1配体对脐带血来源的肥大细胞和人肥大细胞系LAD-2的激活和介质释放的影响。分别用抗原和抗IgE激发豚鼠气管和离体人小支气管，观察SUCNR1对肥大细胞依赖性支气管收缩的影响。
结果：SUCNR1在人肥大细胞上大量表达。采用琥珀酸盐或合成的非代谢物激动剂顺式环氧琥珀酸酯激发，使肥大细胞对IgE依赖的激活过敏，导致脱颗粒和组胺释放增加，二十烷基类化合物的从头合成和细胞因子的分泌。琥珀酸盐增强的肥大细胞反应性可被SUCNR1基因敲除和选择性SUCNR1拮抗剂减弱，并可被药物靶向蛋白激酶C和细胞外信号调节激酶调节。在肥大细胞依赖性豚鼠气道模型中，琥珀酸盐和顺式环氧琥珀酸酯剂量依赖性增强抗原诱导的收缩，并与气管中半胱氨酸白三烯和组胺的生成增加相关。类似地，顺式环氧琥珀酸酯促进了IgE受体诱导的人支气管收缩，其可被SUCNR1拮抗阻断。
结论：SUCNR1增强IgE受体诱导的肥大细胞激活和过敏性支气管收缩，表明该通路在过敏性哮喘加重中起作用，从而将代谢紊乱与肥大细胞依赖性炎症联系起来。
Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction
Xiao Tang, Elin Rönnberg, Jesper Säfholm, Madhuranayaki Thulasingam, Mette Trauelsen, Thue W Schwartz, Craig E Wheelock, Sven-Erik Dahlén, Gunnar Nilsson, Jesper Z Haeggström
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.
OBJECTIVE：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.
背景：SUCNR1是细胞外琥珀酸盐的传感器，琥珀酸盐是一种在氧化应激过程中过量产生的克雷布斯循环中间体，与代谢调节和炎症有关。
目的：虽然肥大细胞表达SUCNR1，但其在肥大细胞反应性和过敏性疾病(如哮喘)中的作用仍有待阐明。
方法：分析SUCNR1配体对脐带血来源的肥大细胞和人肥大细胞系LAD-2的激活和介质释放的影响。分别用抗原和抗IgE激发豚鼠气管和离体人小支气管，观察SUCNR1对肥大细胞依赖性支气管收缩的影响。
结果：SUCNR1在人肥大细胞上大量表达。采用琥珀酸盐或合成的非代谢物激动剂顺式环氧琥珀酸酯激发，使肥大细胞对IgE依赖的激活过敏，导致脱颗粒和组胺释放增加，二十烷基类化合物的从头合成和细胞因子的分泌。琥珀酸盐增强的肥大细胞反应性可被SUCNR1基因敲除和选择性SUCNR1拮抗剂减弱，并可被药物靶向蛋白激酶C和细胞外信号调节激酶调节。在肥大细胞依赖性豚鼠气道模型中，琥珀酸盐和顺式环氧琥珀酸酯剂量依赖性增强抗原诱导的收缩，并与气管中半胱氨酸白三烯和组胺的生成增加相关。类似地，顺式环氧琥珀酸酯促进了IgE受体诱导的人支气管收缩，其可被SUCNR1拮抗阻断。
结论：SUCNR1增强IgE受体诱导的肥大细胞激活和过敏性支气管收缩，表明该通路在过敏性哮喘加重中起作用，从而将代谢紊乱与肥大细胞依赖性炎症联系起来。
(中日友好医院呼吸与危重症医学科 王静茹 摘译 林江涛 审校)
(Allergy. 2022 Feb 4. doi: 10.1111/all.15245.)
(Allergy. 2022 Feb 4. doi: 10.1111/all.15245.)
Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction
Xiao Tang, Elin Rönnberg, Jesper Säfholm, Madhuranayaki Thulasingam, Mette Trauelsen, Thue W Schwartz, Craig E Wheelock, Sven-Erik Dahlén, Gunnar Nilsson, Jesper Z Haeggström
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.
OBJECTIVE：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.
