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Methacholine provocations assess AHR in asthma patients mainly by direct stimulation of smooth muscle cells. Using <jats:italic>in vivo<\/jats:italic> mouse models, mast cells have been implicated in AHR, but the mechanism behind has remained unknown.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Cpa3<jats:italic><jats:sup>Cre<\/jats:sup><\/jats:italic><jats:sup>\/+<\/jats:sup>mice, which lack mast cells, were used to assess the role of mast cells in house dust mite (HDM)\u2010induced experimental asthma. Effects of methacholine in presence or absence of ketanserin were assessed on lung function and in lung mast cells <jats:italic>in vitro<\/jats:italic>. Airway inflammation, mast cell accumulation and activation, smooth muscle proliferation, and HDM\u2010induced bronchoconstriction were evaluated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Repeated intranasal HDM sensitization induced allergic airway inflammation associated with accumulation and activation of lung mast cells. Lack of mast cells, absence of activating Fc\u2010receptors, or antagonizing serotonin (5\u2010HT)<jats:sub>2A<\/jats:sub> receptors abolished HDM\u2010induced trachea contractions. HDM\u2010sensitized mice lacking mast cells had diminished lung\u2010associated 5\u2010HT levels, reduced AHR and methacholine\u2010induced airway contraction, while blocking 5\u2010HT<jats:sub>2A<\/jats:sub> receptors in wild types eliminated AHR, implying that mast cells contribute to AHR by releasing 5\u2010HT. Primary mouse and human lung mast cells express muscarinic M3 receptors. Mouse lung mast cells store 5\u2010HT intracellularly, and methacholine induces release of 5\u2010HT from lung\u2010derived mouse mast cells and Ca<jats:sup>2+<\/jats:sup> flux in human LAD\u20102 mast cells.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Methacholine activates mast cells to release 5\u2010HT, which by acting on 5\u2010HT<jats:sub>2A<\/jats:sub> receptors enhances bronchoconstriction and AHR. Thus, M3\u2010directed asthma treatments like tiotropium may also act by targeting mast cells.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.14748","type":"journal-article","created":{"date-parts":[[2021,1,24]],"date-time":"2021-01-24T10:29:47Z","timestamp":1611484187000},"page":"2057-2069","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":46,"title":["Mast cell\u2010derived serotonin enhances methacholine\u2010induced airway hyperresponsiveness in house dust mite\u2010induced experimental asthma"],"prefix":"10.1111","volume":"76","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2114-2812","authenticated-orcid":false,"given":"Erika","family":"Mendez\u2010Enriquez","sequence":"first","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Perla Abigail","family":"Alvarado\u2010Vazquez","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"Abma","sequence":"additional","affiliation":[{"name":"Unit of Experimental Asthma and Allergy Research Institute of Environmental Medicine (IMM) Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Oscar E.","family":"Simonson","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery and Anaesthesiology Uppsala University Hospital Uppsala Sweden"},{"name":"Department of Surgical Sciences Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergey","family":"Rodin","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery and Anaesthesiology Uppsala University Hospital Uppsala Sweden"},{"name":"Department of Surgical Sciences Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thorsten B.","family":"Feyerabend","sequence":"additional","affiliation":[{"name":"Division for Cellular Immunology Deutsches Krebsforschungszentrum (DKFZ) Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hans\u2010Reimer","family":"Rodewald","sequence":"additional","affiliation":[{"name":"Division for Cellular Immunology Deutsches Krebsforschungszentrum (DKFZ) Heidelberg Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrei","family":"Malinovschi","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christer","family":"Janson","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mikael","family":"Adner","sequence":"additional","affiliation":[{"name":"Unit of Experimental Asthma and Allergy Research Institute of Environmental Medicine (IMM) Karolinska Institutet Stockholm Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3685-5364","authenticated-orcid":false,"given":"Jenny","family":"Hallgren","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2021,3,9]]},"reference":[{"key":"e_1_2_8_2_1","unstructured":"[1]Global Asthma Network.The Global Asthma Report 2018. 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