{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T16:01:16Z","timestamp":1793289676396,"version":"4.5.0"},"reference-count":51,"publisher":"Wiley","issue":"1","license":[{"start":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T00:00:00Z","timestamp":1737676800000},"content-version":"vor","delay-in-days":23,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Immunity Inflam &amp;amp; Disease"],"published-print":{"date-parts":[[2025,1]]},"abstract":"<jats:title>ABSTRACT<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll\u2010like receptor 4 (TLR4) can recognize pathogen\u2010associated\u2010molecular\u2010patterns (PAMPs) and damage\u2010associated molecular patterns (DAMPs); the latter are released during tissue injury. We hypothesized that TLR4 inhibition reduces proinflammatory signaling and cytokine release in: (1) LPS or <jats:italic>Escherichia coli<\/jats:italic>\u2010treated isolated mouse heart; (2) LPS\u2010treated mouse primary adult cardiomyocytes; and (3) the isolated heart during ischemia\u2013reperfusion.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>Isolated C57BL\/6N male mouse hearts were perfused for 120\u2009min, with either LPS, <jats:italic>E. coli<\/jats:italic>, with and without CLI\u2010095 (TLR4 inhibitor). Primary adult mouse cardiomyocytes were treated with LPS or LPS\u2009+\u2009CLI\u2010095. Isolated hearts, exposed to 35\u2009min of global ischemia, were treated with either vehicle or CLI\u2010095 during reperfusion. Infarct size was quantified by triphenyltetrazolium staining. Cytokine expression was analyzed with ELISA, western blot analysis, and qPCR.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>In isolated hearts, <jats:italic>E. coli<\/jats:italic> increased the expression of proinflammatory cytokines (IL\u20106 and CXCL2), which was not attenuated with TLR4 inhibition. TLR4 inhibition reduced expression (<jats:italic>p<\/jats:italic>\u2009=\u20090.004) and release of IL\u20106 (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.0001) in LPS\u2010exposed isolated hearts. LPS activated the nuclear\u2010factor \u03ba\u2010light\u2010chain\u2010enhancer of activated B cells signaling pathway (NF\u2010\u03baB) in primary adult cardiomyocytes. Moreover, TLR4 inhibition reduced LPS\u2010induced mRNA expression and release of IL\u20106 in primary adult cardiomyocytes. Isolated hearts treated with CLI\u2010095 during reperfusion after ischemia (induced DAMPs release) showed reduced infarct size (39\u2009\u00b1\u200917% to 26\u2009\u00b1\u20098%, <jats:italic>p<\/jats:italic>\u2009=\u20090.034) and decreased IL\u20106 release (<jats:italic>p<\/jats:italic>\u2009=\u20090.006).<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>Inhibition of TLR4 reduced proinflammatory signaling and cytokine release in LPS\u2010treated and ischemia\u2013reperfused isolated mouse hearts and in primary adult murine cardiomyocytes.<\/jats:p><\/jats:sec>","DOI":"10.1002\/iid3.70133","type":"journal-article","created":{"date-parts":[[2025,1,24]],"date-time":"2025-01-24T13:25:32Z","timestamp":1737725132000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["TLR4 Inhibition Attenuated LPS\u2010Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes"],"prefix":"10.1002","volume":"13","author":[{"given":"Christine W.","family":"Wiger","sequence":"first","affiliation":[{"name":"Division of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Trine","family":"Ranheim","sequence":"additional","affiliation":[{"name":"Research Institute of Internal Medicine, Oslo University Hospital Oslo Norway"},{"name":"Institute of Clinical Medicine University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1173-4010","authenticated-orcid":false,"given":"Henriette","family":"Arnesen","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo 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Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2962-4143","authenticated-orcid":false,"given":"K\u00e5re\u2010Olav","family":"Stensl\u00f8kken","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"May\u2010Kristin","family":"Torp","sequence":"additional","affiliation":[{"name":"Division of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo Norway"},{"name":"\u00d8stfold Hospital Trust Gr\u00e5lum 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