TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes
ABSTRACT Background Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll‐like receptor 4 (TLR4) can recognize pathogen‐associated‐molecular‐patterns (PAMPs) and damage‐associated molecular patterns (DAMPs); the latter are released during tissue injury. We...
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Wiley
2025-01-01
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| Series: | Immunity, Inflammation and Disease |
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| Online Access: | https://doi.org/10.1002/iid3.70133 |
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| author | Christine W. Wiger Trine Ranheim Henriette Arnesen Jarle Vaage Søren E. Pischke Arne Yndestad Kåre‐Olav Stensløkken May‐Kristin Torp |
| author_facet | Christine W. Wiger Trine Ranheim Henriette Arnesen Jarle Vaage Søren E. Pischke Arne Yndestad Kåre‐Olav Stensløkken May‐Kristin Torp |
| author_sort | Christine W. Wiger |
| collection | DOAJ |
| description | ABSTRACT Background Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll‐like receptor 4 (TLR4) can recognize pathogen‐associated‐molecular‐patterns (PAMPs) and damage‐associated 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 Escherichia coli‐treated isolated mouse heart; (2) LPS‐treated mouse primary adult cardiomyocytes; and (3) the isolated heart during ischemia–reperfusion. Methods Isolated C57BL/6N male mouse hearts were perfused for 120 min, with either LPS, E. coli, with and without CLI‐095 (TLR4 inhibitor). Primary adult mouse cardiomyocytes were treated with LPS or LPS + CLI‐095. Isolated hearts, exposed to 35 min of global ischemia, were treated with either vehicle or CLI‐095 during reperfusion. Infarct size was quantified by triphenyltetrazolium staining. Cytokine expression was analyzed with ELISA, western blot analysis, and qPCR. Results In isolated hearts, E. coli increased the expression of proinflammatory cytokines (IL‐6 and CXCL2), which was not attenuated with TLR4 inhibition. TLR4 inhibition reduced expression (p = 0.004) and release of IL‐6 (p < 0.0001) in LPS‐exposed isolated hearts. LPS activated the nuclear‐factor κ‐light‐chain‐enhancer of activated B cells signaling pathway (NF‐κB) in primary adult cardiomyocytes. Moreover, TLR4 inhibition reduced LPS‐induced mRNA expression and release of IL‐6 in primary adult cardiomyocytes. Isolated hearts treated with CLI‐095 during reperfusion after ischemia (induced DAMPs release) showed reduced infarct size (39 ± 17% to 26 ± 8%, p = 0.034) and decreased IL‐6 release (p = 0.006). Conclusion Inhibition of TLR4 reduced proinflammatory signaling and cytokine release in LPS‐treated and ischemia–reperfused isolated mouse hearts and in primary adult murine cardiomyocytes. |
| format | Article |
| id | doaj-art-f331f8aa365e4faeac1a6721bf4d06f2 |
| institution | Kabale University |
| issn | 2050-4527 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Wiley |
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| series | Immunity, Inflammation and Disease |
| spelling | doaj-art-f331f8aa365e4faeac1a6721bf4d06f22025-02-06T07:50:38ZengWileyImmunity, Inflammation and Disease2050-45272025-01-01131n/an/a10.1002/iid3.70133TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and CardiomyocytesChristine W. Wiger0Trine Ranheim1Henriette Arnesen2Jarle Vaage3Søren E. Pischke4Arne Yndestad5Kåre‐Olav Stensløkken6May‐Kristin Torp7Division of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo NorwayResearch Institute of Internal Medicine, Oslo University Hospital Oslo NorwayDivision of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo NorwayDivision of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo NorwayInstitute of Clinical Medicine University of Oslo Oslo NorwayResearch Institute of Internal Medicine, Oslo University Hospital Oslo NorwayDivision of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo NorwayDivision of Physiology, Department of Molecular Medicine Institute of Basic Medical Sciences University of Oslo Oslo NorwayABSTRACT Background Sepsis is associated with myocardial injury and early mortality. The innate immune receptor Toll‐like receptor 4 (TLR4) can recognize pathogen‐associated‐molecular‐patterns (PAMPs) and damage‐associated 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 Escherichia coli‐treated isolated mouse heart; (2) LPS‐treated mouse primary adult cardiomyocytes; and (3) the isolated heart during ischemia–reperfusion. Methods Isolated C57BL/6N male mouse hearts were perfused for 120 min, with either LPS, E. coli, with and without CLI‐095 (TLR4 inhibitor). Primary adult mouse cardiomyocytes were treated with LPS or LPS + CLI‐095. Isolated hearts, exposed to 35 min of global ischemia, were treated with either vehicle or CLI‐095 during reperfusion. Infarct size was quantified by triphenyltetrazolium staining. Cytokine expression was analyzed with ELISA, western blot analysis, and qPCR. Results In isolated hearts, E. coli increased the expression of proinflammatory cytokines (IL‐6 and CXCL2), which was not attenuated with TLR4 inhibition. TLR4 inhibition reduced expression (p = 0.004) and release of IL‐6 (p < 0.0001) in LPS‐exposed isolated hearts. LPS activated the nuclear‐factor κ‐light‐chain‐enhancer of activated B cells signaling pathway (NF‐κB) in primary adult cardiomyocytes. Moreover, TLR4 inhibition reduced LPS‐induced mRNA expression and release of IL‐6 in primary adult cardiomyocytes. Isolated hearts treated with CLI‐095 during reperfusion after ischemia (induced DAMPs release) showed reduced infarct size (39 ± 17% to 26 ± 8%, p = 0.034) and decreased IL‐6 release (p = 0.006). Conclusion Inhibition of TLR4 reduced proinflammatory signaling and cytokine release in LPS‐treated and ischemia–reperfused isolated mouse hearts and in primary adult murine cardiomyocytes.https://doi.org/10.1002/iid3.70133DAMPsheartinflammationLPSPAMPssepsis |
| spellingShingle | Christine W. Wiger Trine Ranheim Henriette Arnesen Jarle Vaage Søren E. Pischke Arne Yndestad Kåre‐Olav Stensløkken May‐Kristin Torp TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes Immunity, Inflammation and Disease DAMPs heart inflammation LPS PAMPs sepsis |
| title | TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes |
| title_full | TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes |
| title_fullStr | TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes |
| title_full_unstemmed | TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes |
| title_short | TLR4 Inhibition Attenuated LPS‐Induced Proinflammatory Signaling and Cytokine Release in Mouse Hearts and Cardiomyocytes |
| title_sort | tlr4 inhibition attenuated lps induced proinflammatory signaling and cytokine release in mouse hearts and cardiomyocytes |
| topic | DAMPs heart inflammation LPS PAMPs sepsis |
| url | https://doi.org/10.1002/iid3.70133 |
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