Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress

Thaddeus T. Schug, Qing Xu, Huiming Gao, Ashwin Peres-da-Silva, David W. Draper, Michael B. Fessler, Aparna Purushotham, Xiaoling Li

Research output: Contribution to journalArticle

Abstract

Macrophage activation and infiltration into resident tissues is known to mediate local inflammation and is a hallmark feature of metabolic syndrome. Members of the sirtuin family of proteins regulate numerous physiological processes, including those involved in nutrient regulation and the promotion of longevity. However, the important role that SIRT1, the leading sirtuin family member, plays in immune response remains unclear. In this study, we demonstrate that SIRT1 modulates the acetylation status of the RelA/p65 subunit of NF-κB and thus plays a pivotal role in regulating the inflammatory, immune, and apoptotic responses in mammals. Using a myeloid cell-specific SIRT1 knockout (Mac-SIRT1 KO) mouse model, we show that ablation of SIRT1 in macrophages renders NF-κB hyperacetylated, resulting in increased transcriptional activation of proinflammatory target genes. Consistent with increased proinflammatory gene expression, Mac-SIRT1 KO mice challenged with a high-fat diet display high levels of activated macrophages in liver and adipose tissue, predisposing the animals to development of systemic insulin resistance and metabolic derangement. In summary, we report that SIRT1, in macrophages, functions to inhibit NF-κB-mediated transcription, implying that myeloid cell-specific modulation of this sirtuin may be beneficial in the treatment of inflammation and its associated diseases.

Original languageEnglish (US)
Pages (from-to)4712-4721
Number of pages10
JournalMolecular and Cellular Biology
Volume30
Issue number19
DOIs
StatePublished - Oct 2010
Externally publishedYes

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Macrophages
Myeloid Cells
Physiological Phenomena
Inflammation
Macrophage Activation
High Fat Diet
Acetylation
Transcriptional Activation
Insulin Resistance
Adipose Tissue
Mammals
Gene Expression
Food
Liver
Genes
Proteins
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

Schug, T. T., Xu, Q., Gao, H., Peres-da-Silva, A., Draper, D. W., Fessler, M. B., ... Li, X. (2010). Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. Molecular and Cellular Biology, 30(19), 4712-4721. https://doi.org/10.1128/MCB.00657-10

Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. / Schug, Thaddeus T.; Xu, Qing; Gao, Huiming; Peres-da-Silva, Ashwin; Draper, David W.; Fessler, Michael B.; Purushotham, Aparna; Li, Xiaoling.

In: Molecular and Cellular Biology, Vol. 30, No. 19, 10.2010, p. 4712-4721.

Research output: Contribution to journalArticle

Schug, TT, Xu, Q, Gao, H, Peres-da-Silva, A, Draper, DW, Fessler, MB, Purushotham, A & Li, X 2010, 'Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress', Molecular and Cellular Biology, vol. 30, no. 19, pp. 4712-4721. https://doi.org/10.1128/MCB.00657-10
Schug, Thaddeus T. ; Xu, Qing ; Gao, Huiming ; Peres-da-Silva, Ashwin ; Draper, David W. ; Fessler, Michael B. ; Purushotham, Aparna ; Li, Xiaoling. / Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress. In: Molecular and Cellular Biology. 2010 ; Vol. 30, No. 19. pp. 4712-4721.
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