The Sirt1 Activator SRT1720 Mitigates Human Monocyte Activation and Improves Outcome During Gram-Negative Pneumosepsis in Mice

Community-acquired pneumonia (CAP) is a leading cause of death, with mortality linked to an unbalanced host response. Sirtuin (Sirt)1, a histone deacetylase, regulating metabolism and epigenetics, may be fundamental in activating the innate immune response. Sirt1 mRNA expression was significantly re...

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Vydáno v:	International journal of molecular sciences Ročník 26; číslo 19; s. 9309
Hlavní autoři:	Blot, Mathieu, Léopold, Valentine, de Beer, Regina, Florquin, Sandrine, Butler, Joe M., van’t Veer, Cornelis, de Vos, Alex F., van der Poll, Tom
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	Switzerland MDPI AG 01.10.2025
Témata:	Aged Analysis Animals Apoptosis Bacterial pneumonia Blood clots Cytokines Disease Models, Animal Epigenetic inheritance Female Heterocyclic Compounds, 4 or More Rings - pharmacology Heterocyclic Compounds, 4 or More Rings - therapeutic use Humans Immune response Infections Inflammation Interleukin-6 - metabolism Liver Lung - microbiology Lung - pathology Lungs Male Metabolism Mice Middle Aged Monocytes - drug effects Monocytes - immunology Monocytes - metabolism Neutrophils Pathogens Pathology Patient outcomes Physiological aspects Plasma Pneumonia Pneumonia, Bacterial - drug therapy RNA Sepsis Sirtuin 1 - genetics Sirtuin 1 - metabolism THP-1 Cells Netherlands France United States Illinois SRT1720 monocyte activation pneumonia immune response Sirt1 lipopolysaccharide Klebsiella pneumoniae
ISSN:	1422-0067, 1661-6596, 1422-0067
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Shrnutí:	Community-acquired pneumonia (CAP) is a leading cause of death, with mortality linked to an unbalanced host response. Sirtuin (Sirt)1, a histone deacetylase, regulating metabolism and epigenetics, may be fundamental in activating the innate immune response. Sirt1 mRNA expression was significantly reduced in monocytes from CAP patients (n = 76) upon admission compared to healthy controls (n = 42), with levels returning to normal after 30 days. Pharmacological activation of Sirt1 with SRT1720 decreased LPS- and K. pneumoniae-induced IL-6 release in primary human monocytes and decreased NF-κB activation in THP1 cells. In a mouse K. pneumoniae pneumosepsis model, SRT1720 strongly reduced neutrophil influx and degranulation markers in bronchoalveolar lavage fluid, lowered pulmonary concentrations of IL-6 and TNF-α, and reduced lung pathology scores. Simultaneously, it reduced neutrophil content in liver tissue and plasma transaminase levels, alongside a trend toward reduced liver necrosis. Plasma IL-6 and TNF-α were significantly lower in SRT1720-treated mice at 42 h. Finally, while SRT1720 did not impact bacterial loads in the lungs, it reduced bacterial burden in blood, with a similar trend observed in liver homogenates. In conclusion, the Sirt1 activator SRT1720 exerts anti-inflammatory effects on human monocytes, reduces local and systemic inflammation and organ injury, and diminishes bacterial dissemination in murine pneumosepsis.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	1422-0067 1661-6596 1422-0067
DOI:	10.3390/ijms26199309