Abstract
The human body has a remarkable ability to regulate inflammation, a biophysical response triggered by virus infection and tissue damage. Sirt6 is critical for metabolism and lifespan; however, its role in inflammation is unknown. Here we show that Sirt6-null (Sirt6(-/-)) mice developed chronic liver inflammation starting at ∼2 months of age, and all animals were affected by 7-8 months of age. Deletion of Sirt6 in T cells or myeloid-derived cells was sufficient to induce liver inflammation and fibrosis, albeit to a lesser degree than that in the global Sirt6(-/-) mice, suggesting that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6(-/-) mice showed increased MCP-1, IL-6, and TNFα expression levels and were hypersensitive to LPS stimulation. Mechanistically, SIRT6 interacts with c-JUN and deacetylates histone H3 lysine 9 (H3K9) at the promoter of proinflammatory genes whose expression involves the c-JUN signaling pathway. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression. These data suggest that Sirt6 plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes.
Highlights
Sirt6 plays important roles in metabolism and lifespan; its role in inflammation is unknown
Liver Inflammation Is Primarily Caused by Sirt6 Deficiency in the Lymphocytes and Myeloid-derived Cells Rather than in the Hepatocytes—Because the inflammation occurred primarily in the liver, we investigated whether the absence of Sirt6 in hepatocytes is a primary cause for the inflammation
We revealed that Sirt6Ϫ/Ϫ mice developed invariably chronic liver inflammation starting at ϳ2 months of age
Summary
Sirt plays important roles in metabolism and lifespan; its role in inflammation is unknown. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression These data suggest that Sirt plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes. Sirt Plays an Anti-inflammatory Role of homozygous mice died before 4 weeks of age when they were in a mixed genetic background of 129/Black Swiss/FVB [28] Analysis of these mutant mice demonstrated that Sirt negatively regulates AKT phosphorylation at Ser-473 and Thr-308 through inhibition of multiple upstream molecules, including insulin receptor, IRS1, and IRS2. We further demonstrate that the absence of Sirt results in activation of c-JUN-dependent transcription and enhanced expression of proinflammatory genes in immune cells, leading to chronic inflammation and fibrosis in the liver of mutant mice
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