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While mast cells express SUCNR1, its role in mast cell reactivity and allergic conditions such as asthma remains to be elucidated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cord blood\u2010derived mast cells and human mast cell line LAD\u20102 challenged by SUCNR1\u00a0ligands were analyzed for the activation and mediator release. Effects on mast cell\u2010dependent bronchoconstriction were assessed in guinea pig trachea and isolated human small bronchi challenged with antigen and anti\u2010IgE, respectively.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>SUCNR1 is abundantly expressed on human mast cells. Challenge with succinate, or the synthetic non\u2010metabolite agonist cis\u2010epoxysuccinate, renders mast cells hypersensitive to IgE\u2010dependent activation, resulting in augmented degranulation and histamine release, de novo biosynthesis of eicosanoids and cytokine secretion. The succinate\u2010potentiated mast cell reactivity was attenuated by SUCNR1\u00a0knockdown and selective SUCNR1 antagonists and could be tuned by pharmacologically targeting protein kinase C and extracellular signal\u2010regulated kinase. Both succinate and cis\u2010epoxysuccinate dose\u2010dependently potentiated antigen\u2010induced contraction in a mast cell\u2010dependent guinea pig airway model, associated with increased generation of cysteinyl\u2010leukotrienes and histamine in trachea. Similarly, cis\u2010epoxysuccinate aggravated IgE\u2010receptor\u2010induced contraction of human bronchi, which was blocked by SUCNR1 antagonism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>SUCNR1 amplifies IgE\u2010receptor\u2010induced mast cell activation and allergic bronchoconstriction, suggesting a role for this pathway in aggravation of allergic asthma, thus linking metabolic perturbations to mast cell\u2010dependent inflammation.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.15245","type":"journal-article","created":{"date-parts":[[2022,2,5]],"date-time":"2022-02-05T06:43:25Z","timestamp":1644043405000},"page":"2677-2687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Activation of succinate receptor 1 boosts human mast cell reactivity and allergic bronchoconstriction"],"prefix":"10.1111","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2918-7748","authenticated-orcid":false,"given":"Xiao","family":"Tang","sequence":"first","affiliation":[{"name":"Division of Physiological Chemistry II Department of Medical Biochemistry and Biophysics Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4628-9968","authenticated-orcid":false,"given":"Elin","family":"R\u00f6nnberg","sequence":"additional","affiliation":[{"name":"Division of Immunology and Allergy Department of Medicine Solna Karolinska Institutet, and Karolinska University Hospital  Solna Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jesper","family":"S\u00e4fholm","sequence":"additional","affiliation":[{"name":"Unit of Experimental Asthma and Allergy Research Institute of Environmental Medicine Karolinska Institutet  Stockholm 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Biophysics Karolinska Institutet  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sven\u2010Erik","family":"Dahl\u00e9n","sequence":"additional","affiliation":[{"name":"Unit of Experimental Asthma and Allergy Research Institute of Environmental Medicine Karolinska Institutet  Stockholm Sweden"},{"name":"Department of Respiratory Medicine Karolinska University Hospital Huddinge  Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6795-5512","authenticated-orcid":false,"given":"Gunnar","family":"Nilsson","sequence":"additional","affiliation":[{"name":"Division of Immunology and Allergy Department of Medicine Solna Karolinska Institutet, and Karolinska University Hospital  Solna Sweden"},{"name":"Department of Medical Sciences Uppsala University  Uppsala 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