Sirt1 restrains lung inflammasome activation in a murine model of sepsis

Rong Gao, Zhongsen Ma, Yuxin Hu, Jiao Chen, Sreerama Shetty, Jian Fu

Research output: Contribution to journalArticlepeer-review

98 Scopus citations

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-kB, 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.

Original languageEnglish
Pages (from-to)L847-L853
JournalAmerican Journal of Physiology - Lung Cellular and Molecular Physiology
Volume308
Issue number8
DOIs
StatePublished - 2015

Bibliographical note

Publisher Copyright:
© 2015, American Physiological Society. All rights reserved.

Keywords

  • Caspase
  • Inflammation
  • Interleukin-1
  • Lung
  • Transcription factor

ASJC Scopus subject areas

  • Physiology
  • Pulmonary and Respiratory Medicine
  • Physiology (medical)
  • Cell Biology

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