Myeloid deletion of SIRT1 induces inflammatory signaling in response to environmental stress.
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.
Schug
Thaddeus T
TT
Laboratory of Signal Transduction, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA. schugt@niehs.nih.gov
Xu
Qing
Q
Gao
Huiming
H
Peres-da-Silva
Ashwin
A
Draper
David W
DW
Fessler
Michael B
MB
Purushotham
Aparna
A
Li
Xiaoling
X
D000107:Acetylation; D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004041:Dietary Fats / Q000008:administration & dosage; D018149:Glucose Intolerance / Q000235:genetics / Q000378:metabolism; D051548:Histone Acetyltransferases / Q000378:metabolism; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D007739:L Cells; D008262:Macrophage Activation / Q000187:drug effects; D008264:Macrophages / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000378:metabolism; D034622:RNA Interference; D015398:Signal Transduction; D056564:Sirtuin 1 / Q000235:genetics / Q000378:metabolism*; D051996:Transcription Factor RelA / Q000235:genetics / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D016207:Cytokines; D004041:Dietary Fats; D051996:Transcription Factor RelA; D014409:Tumor Necrosis Factor-alpha; D051548:Histone Acetyltransferases; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1