Sirt1 restrains lung inflammasome activation in a murine model of sepsis.

Abstract

Excessive inflammation is a major cause of organ damage during sepsis. The elderly are highly susceptible to sepsis-induced organ injury. Sirt1 expression is reduced during aging. In the present study, we investigated the role of Sirt1, a histone deacetylase, in controlling inflammatory responses in a murine sepsis model induced by cecal ligation and puncture (CLP). We examined lung inflammatory signaling in inducible Sirt1 knockout (Sirt1(-/-)) mice and wild-type littermates (Sirt1(+/+)) after CLP. Our results demonstrated that Sirt1 deficiency led to severe lung inflammatory injury. To further investigate molecular mechanisms of Sirt1 regulation of lung inflammatory responses in sepsis, we conducted a series of experiments to assess lung inflammasome activation after CLP. We detected increased lung inflammatory signaling including NF-κB, signal transducer and activator of transcription 3, and ERK1/2 activation in Sirt1(-/-) mice after CLP. Furthermore, inflammasome activity was increased in Sirt1(-/-) mice after CLP, as demonstrated by increased IL-1β and caspase-7 cleavage and activation. Aggravated inflammasome activation in Sirt1(-/-) mice was associated with the increased production of lung proinflammatory mediators, including ICAM-1 and high-mobility group box 1, and further disruption of tight junctions and adherens junctions, as demonstrated by dramatic reduction of lung claudin-1 and vascular endothelial-cadherin expression, which was associated with the upregulation of matrix metallopeptidase 9 expression. In summary, our results suggest that Sirt1 suppresses acute lung inflammation during sepsis by controlling inflammasome activation pathway.

• Authors: Rong Gao, Zhongsen Ma, Yuxin Hu, Jiao Chen, Sreerama Shetty, Jian Fu
• Journal: American journal of physiology. Lung cellular and molecular physiology (Am J Physiol Lung Cell Mol Physiol) Vol. 308 Issue 8 Pg. L847-53 (Apr 15 2015) ISSN: 1522-1504 [Electronic] United States
• PMID: 25659903 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2015 the American Physiological Society.

Chemical References

• HMGB1 Protein
• HMGB1 protein, mouse
• Icam1 protein, mouse
• Inflammasomes
• Intercellular Adhesion Molecule-1
• Casp3 protein, mouse
• Casp7 protein, mouse
• Caspase 3
• Caspase 7
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse
• Sirt1 protein, mouse
• Sirtuin 1

Topics

• Animals
• Caspase 3 (metabolism)
• Caspase 7 (metabolism)
• Disease Models, Animal
• Female
• HMGB1 Protein (metabolism)
• Humans
• Inflammasomes (metabolism)
• Intercellular Adhesion Molecule-1 (metabolism)
• Lung (enzymology, immunology)
• Matrix Metalloproteinase 9 (metabolism)
• Mice, Knockout
• Sepsis (enzymology, immunology)
• Sirtuin 1 (physiology)