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.

SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

“…However, the role of SIRT1 in sepsis is rarely studied and its exact mechanism is yet to be determined. Recently, a study showed that SIRT1 knockdown mice exhibited aggravated inflammatory signaling such as NF-kappa B in lung tissue of CLP mice [10]. Furthermore, pharmacological SIRT1 activation decreased mortality in experimental sepsis [24].…”

“…Through deacetylation of histone and nonhistone substrate, SIRT1 is involved in various metabolic and inflammatory diseases [8, 9]. Interestingly, SIRT1 activity is decreased in the liver, spleen, small bowel, and lung tissue in experimental sepsis models, and SIRT1 activation could improve the outcome of sepsis and ameliorate the associated inflammatory response [10, 11]. Besides SIRT1, another sirtuin, SIRT3, has also received considerable attention [12, 13].…”

Selective HDAC6 inhibition prevents TNF-α-induced lung endothelial cell barrier disruption and endotoxin-induced pulmonary edema

“…The coverslips were mounted on the slides with DAPI. Immunoblotting assays of cell and lung tissue samples were conducted as described previously (15,16). Image analysis was carried out with the ImageJ program (v1.50i; National Institutes of Health, Bethesda, MD).…”

“…Experiments were terminated 24 h after LPS challenge. Lung wet/dry weight ratio was assessed as described previously (16).…”

SRT1720, a sirtuin 1 activator, attenuates organ injury and inflammation in sepsis

“…have demonstrated increased inflammasome activity in the lung of Sirt1-deficient mice compared to wild-type littermates after CLP. 40 The transcription activation of inflammasome components like NLRP3 can be regulated by active nf-kb which in turn is inhibited by Srt1 activation. 41,42 …”