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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Published in:International journal of molecular sciences Vol. 26; no. 19; p. 9309
Main Authors: Blot, Mathieu, Léopold, Valentine, de Beer, Regina, Florquin, Sandrine, Butler, Joe M., van’t Veer, Cornelis, de Vos, Alex F., van der Poll, Tom
Format: Journal Article
Language:English
Published: Switzerland MDPI AG 01.10.2025
Subjects:
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
Online Access:Get full text
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Summary: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.
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ISSN:1422-0067
1661-6596
1422-0067
DOI:10.3390/ijms26199309