{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,19]],"date-time":"2026-10-19T17:46:05Z","timestamp":1792431965311,"version":"4.5.0"},"reference-count":35,"publisher":"Wiley","issue":"11","license":[{"start":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T00:00:00Z","timestamp":1659571200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004063","name":"Knut och Alice Wallenbergs Stiftelse","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004063","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002794","name":"Cancerfonden","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100002794","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004359","name":"Vetenskapsr\u00e5det","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100004359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Experimental Dermatology"],"published-print":{"date-parts":[[2022,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mastocytosis is a KIT\u2010related myeloproliferative disease characterised by abnormal expansion of neoplastic mast cells (MC) in the skin or virtually any other organ system. The cutaneous form of adult\u2010onset mastocytosis is almost invariably combined with indolent systemic involvement for which curative therapy is yet not available. Here we evaluated a concept of depleting cutaneous MCs in mastocytosis lesions ex vivo by targeting their secretory granules. Skin biopsies from mastocytosis patients were incubated with or without mefloquine, an antimalarial drug known to penetrate into acidic organelles such as MC secretory granules. Mefloquine reduced the number of dermal MCs without affecting keratinocyte proliferation or epidermal gross morphology at drug concentrations up to 40\u2009\u03bcM. Flow cytometric analysis of purified dermal MCs showed that mefloquine\u2010induced cell death was mainly due to apoptosis and accompanied by caspase\u20103 activation. However, caspase inhibition provided only partial protection against mefloquine\u2010induced cell death, indicating predominantly caspase\u2010independent apoptosis. Further assessments revealed that mefloquine caused an elevation of granule pH and a corresponding decrease in cytosolic pH, suggesting drug\u2010induced granule permeabilisation. Extensive damage to the MC secretory granules was confirmed by transmission electron microscopy analysis. Further, blockade of granule acidification or serine protease activity prior to mefloquine treatment protected MCs from apoptosis, indicating that granule acidity and granule\u2010localised serine proteases play major roles in the execution of mefloquine\u2010induced cell death. Altogether, these findings reveal that mefloquine induces selective apoptosis of MCs by targeting their secretory granules and suggest that the drug may potentially extend its range of medical applications.<\/jats:p>","DOI":"10.1111\/exd.14651","type":"journal-article","created":{"date-parts":[[2022,7,25]],"date-time":"2022-07-25T12:29:57Z","timestamp":1658752197000},"page":"1729-1740","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["Mefloquine causes selective mast cell apoptosis in cutaneous mastocytosis lesions by a secretory <scp>granule\u2010mediated<\/scp> pathway"],"prefix":"10.1111","volume":"31","author":[{"given":"Maria","family":"Lampinen","sequence":"first","affiliation":[{"name":"Department of Medical Sciences, Dermatology and Venereology Uppsala University  Uppsala Sweden"},{"name":"Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Hagforsen","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Dermatology and Venereology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simone","family":"Westr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Dermatology and Venereology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Bergstr\u00f6m","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Dermatology and Venereology Uppsala University  Uppsala Sweden"},{"name":"Department of Dermatology Uppsala University Hospital  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kerstin\u00a0Hamberg","family":"Levedahl","sequence":"additional","affiliation":[{"name":"Department of Public Health and Caring Sciences Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aida","family":"Paivandy","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola","family":"Lara\u2010Valencia","sequence":"additional","affiliation":[{"name":"Department of Immunology, Genetics and Pathology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gunnar","family":"Pejler","sequence":"additional","affiliation":[{"name":"Department of Medical Biochemistry and Microbiology Uppsala University  Uppsala Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1677-1665","authenticated-orcid":false,"given":"Ola","family":"Rollman","sequence":"additional","affiliation":[{"name":"Department of Medical Sciences, Dermatology and 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