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They can induce inflammasome activation and pyroptosis in macrophages, suggesting cytotoxicity, which remains to be elucidated in human tissues.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Experimental Approach<\/jats:title>\n                    <jats:p>\n                      To determine the cell\u2010type specificity of this cytotoxicity, we used human monocyte\u2010derived macrophages and non\u2010adherent peripheral blood cells from healthy donors, plus omental white adipose tissue, stromal vascular fraction\u2010derived pre\u2010adipocytes and adipocytes from obese patients undergoing bariatric surgery. All these cells\/tissues were treated with nanomolar concentrations of ouabain (50, 100, 500\u2009nM) to investigate the level of cytotoxicity and the mechanisms leading to cell death. In white adipose tissue, we investigated ouabain\u2010mediated cytotoxicity by measuring insulin sensitivity, adipose tissue function and extracellular matrix deposition\n                      <jats:italic>ex vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Key Results<\/jats:title>\n                    <jats:p>\n                      Ouabain induced cell death through pyroptosis and apoptosis, and was more effective in monocyte\u2010derived macrophages compared to non\u2010adherent peripheral blood mononuclear cell populations. This cytotoxicity is dependent on K\n                      <jats:sup>+<\/jats:sup>\n                      flux, as ouabain causes intracellular depletion of K\n                      <jats:sup>+<\/jats:sup>\n                      and accumulation of Na\n                      <jats:sup>+<\/jats:sup>\n                      and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      . Consistently, the cell death caused by these ion imbalances can be rescued by addition of potassium chloride to human monocyte\u2010derived macrophages. Remarkably, when white adipose tissue explants from obese patients are cultured with nanomolar concentrations of ouabain, this causes depletion of macrophages, down\u2010regulation of type VI collagen levels and amelioration of insulin sensitivity\n                      <jats:italic>ex vivo<\/jats:italic>\n                      .\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion and Implications<\/jats:title>\n                    <jats:p>The use of nanomolar concentration of cardiac glycosides could be an attractive therapeutic treatment for metabolic syndrome, characterized by pathogenic infiltration and activation of macrophages.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>LINKED ARTICLES<\/jats:title>\n                    <jats:p>\n                      This article is part of a themed issue on Inflammation, Repair and Ageing. To view the other articles in this section visit\n                      <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" xlink:href=\"http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.9\/issuetoc\">http:\/\/onlinelibrary.wiley.com\/doi\/10.1111\/bph.v179.9\/issuetoc<\/jats:ext-link>\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/bph.15423","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T23:05:08Z","timestamp":1614899108000},"page":"1874-1886","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Cardiac glycosides cause cytotoxicity in human macrophages and ameliorate white adipose tissue homeostasis"],"prefix":"10.1111","volume":"179","author":[{"given":"Antoni","family":"Olona","sequence":"first","affiliation":[{"name":"Centre for Inflammatory Disease Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Charlotte","family":"Hateley","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Disease Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4622-9201","authenticated-orcid":false,"given":"Ana","family":"Guerrero","sequence":"additional","affiliation":[{"name":"MRC London Institute of Medical Sciences (LMS)  London UK"},{"name":"Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeong\u2010Hun","family":"Ko","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Disease Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael R.","family":"Johnson","sequence":"additional","affiliation":[{"name":"Division of Brain Sciences Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2503-3653","authenticated-orcid":false,"given":"Paras K.","family":"Anand","sequence":"additional","affiliation":[{"name":"Department of Infectious Disease Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"David","family":"Thomas","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Disease Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jesus","family":"Gil","sequence":"additional","affiliation":[{"name":"MRC London Institute of Medical Sciences (LMS)  London UK"},{"name":"Institute of Clinical Sciences (ICS), Faculty of Medicine Imperial College London  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jacques","family":"Behmoaras","sequence":"additional","affiliation":[{"name":"Centre for Inflammatory Disease Imperial College London, Hammersmith Hospital  London UK"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2021,5,3]]},"reference":[{"key":"e_1_2_12_2_1","doi-asserted-by":"publisher","DOI":"10.1016\/0002-8703(81)90100-9"},{"key":"e_1_2_12_3_1","doi-asserted-by":"publisher","DOI":"10.1111\/bph.14112"},{"issue":"1","key":"e_1_2_12_4_1","first-page":"S1","article-title":"The Concise Guide to PHARMACOLOGY 2019\/20: Introduction and other protein targets","volume":"176","author":"Alexander S. 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