Sirt6 regulates dendritic cell differentiation, maturation, and function

Lasigliè, Denise; Boero, Silvia; Bauer, Inga; Morando, Sara; Damonte, Patrizia; Cea, Michele; Monacelli, Fiammetta; Odetti, Patrizio; Ballestrero, Alberto; Bertolotto, Antonio; Mostoslavsky, Raul; Poggi, Alessandro; Nencioni, Alessio

doi:10.18632/aging.100870

Cited by 26 publications

(27 citation statements)

References 39 publications

(101 reference statements)

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“…Emerging evidence suggests that SIRT6, as a unique chromatin-associated deacetylase, share some of SIRT1-mediated protective effects [ 9 , 11 - 15 ], such as inhibiting heart failure [ 16 ] and decelerating aging process [ 17 ] in mice. SIRT6 also halts endothelial inflammation [ 18 ], aging [ 19 - 21 ], as well as regulates dendritic cell differentiation, maturation and function [ 22 ]. In addition, SIRT6 expression is decreased in endothelial cells (ECs) under chronic stimulation with lipopolysaccharide (LPS) [ 18 ], hydrogen peroxide (H 2 O 2) [ 21 ] and high glucose [ 23 - 25 ], three of which are risk factors associated with endothelial dysfunction and atherogenesis.…”

Section: Introductionmentioning

confidence: 99%

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Yin

Koroleva

et al. 2016

Aging

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SIRT6 is an important member of sirtuin family that represses inflammation, aging and DNA damage, three of which are causing factors for endothelial dysfunction. SIRT6 expression is decreased in atherosclerotic lesions from ApoE−/− mice and human patients. However, the role of SIRT6 in regulating vascular endothelial function and atherosclerosis is not well understood. Here we show that SIRT6 protects against endothelial dysfunction and atherosclerosis. Global and endothelium-specific SIRT6 knockout mice exhibited impaired endothelium-dependent vasorelaxation. Moreover, SIRT6+/− haploinsufficient mice fed a high-fat diet (HFD) also displayed impaired endothelium-dependent vasorelaxation. Importantly, SIRT6+/−;ApoE−/− mice after HFD feeding exhibited exacerbated atherosclerotic lesion development, concurrent with increased expression of the proinflammatory cytokine VCAM-1. Loss- and gain-of-SIRT6 function studies in cultured human endothelial cells (ECs) showed that SIRT6 attenuated monocyte adhesion to ECs. RNA-sequencing profiling revealed that SIRT6 overexpression decreased the expression of multiple atherosclerosis-related genes, including proatherogenic gene TNFSF4 (tumor necrosis factor superfamily member 4). Chromatin immunoprecipitation assays showed that SIRT6 decreased TNFSF4 gene expression by binding to and deacetylating H3K9 at TNFSF4 gene promoter. Collectively, these findings demonstrate that SIRT6 play a pivotal role in maintaining endothelial function and increased SIRT6 activity could be a new therapeutic strategy to combat atherosclerotic disease.

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Section: Introductionmentioning

confidence: 99%

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Yin

Koroleva

et al. 2016

Aging

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“…Accordingly, Sirt5 –/– mice show a reduced inflammatory cytokine response during sepsis . Sirt6 is important for TNF‐α production and dendritic cell function . Sirt7 –/– mice show a shortened lifespan and due to cardiac failure, cardiac myocyte apoptosis mediated by p53 hyperacetylation, with myocardial infiltrates of granulocytes and T cells .…”

Section: The Role Of Other Sirtuins In the Immune Systemmentioning

confidence: 99%

“…79 Sirt6 is important for TNF-production 80 and dendritic cell function. 81 Sirt7 -/mice show a shortened lifespan and due to cardiac failure, cardiac myocyte apoptosis mediated by p53 hyperacetylation, with myocardial infiltrates of granulocytes and T cells. 82 In addition to cardiac myocyte apoptosis, these findings also raised the question if Sirt7 may have immunoregulatory functions.…”

Section: The Role Of Other Sirtuins In the Immune Systemmentioning

confidence: 99%

Sirtuin-1 in immunotherapy: A Janus-headed target

Chadha

Wang

Hancock

et al. 2019

Journal of Leukocyte Biology

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Sirtuin‐1 (Sirt1), a member of the NAD‐dependent sirtuin family of histone/protein deacetylases (HDAC), is an important target for immunotherapy due to its role in deacetylating the transcription factors Foxp3 and thymic retinoid acid receptor related orphan receptor gamma (RORγt). Sirt1 inhibition can increase Foxp3 acetylation and promote the production and functions of Foxp3+ T‐regulatory (Treg) cells, whereas the acetylation of RORγt decreases its transcriptional activity DNA binding and decreases the differentiation of proinflammatory Th17 cells. Pharmacologic inhibitors of Sirt1 increase allograft survival and decrease autoimmune colitis and experimental allergic encephalomyelitis. However, in contrast to its role in T cells, Sirt1 has anti‐inflammatory effects in myeloid cells, and, context dependent, in Th17 cells. Here, inhibition of Sirt1 can have proinflammatory effects. In addition to effects arising from the central role of Sirt1 in cellular metabolism and NAD‐dependent reactions, such proinflammatory effects further complicate the potential of Sirt1 for therapeutic immunosuppression. This review aims to reconcile the opposing literature on pro‐ and anti‐inflammatory effects of Sirt1, provides an overview of the role of Sir1 in the immune system, and discusses the pros and cons associated with inhibiting Sirt1 for control of inflammation and immune responses.

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“…Lysine fatty acylation helps to target TNF-α to lysosomes instead of to the endosomal/secretory pathway [104]. In addition, SIRT6 controls the differentiation and maturation of dendritic cells, as SIRT6 knockout mice display low frequencies of bone marrow dendritic cell precursors and low yields of bone marrow-derived dendritic cells compared to wild-type mice, but increased frequencies of granulocytes and macrophages [105]. SIRT6 knockout dendritic cells were also shown to be immature.…”

Section: Sirtuins As Metabolic Sensors That Regulate Inflammationmentioning

confidence: 99%

“…SIRT6 knockout dendritic cells were also shown to be immature. Interestingly, the capacity of those cells to secrete TNF-α and IL-6 was reduced in response to some Toll-like receptor ligands, but increased in response to others, suggesting that under some circumstances the inhibitory effects of SIRT6 on the NF-κB pathway may overcome the stimulatory effects of SIRT6 on direct TNF-α secretion [105]. …”

Section: Sirtuins As Metabolic Sensors That Regulate Inflammationmentioning

confidence: 99%

The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

Traba¹,

Sack²

2016

Cell. Mol. Life Sci.

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Sterile inflammation is a cornerstone of immune activation in obesity and type 2 Diabetes Mellitus. The molecular underpinnings of this inflammation include nutrient excess-mediated activation of the innate immune NLRP3 inflammasome. At the same time, disruption of mitochondrial integrity is emerging as an integral control node in NLRP3 inflammasome activation and is also associated with caloric overload conditions including obesity and diabetes. Conversely, caloric restriction and fasting mimetic interventions alleviate these caloric excess-linked diseases and reduce inflammation and the NLRP3 inflammasome. The objective of this review is to integrate the findings linking mitochondrial integrity to the activation of the NLRP3 inflammasome and to evaluate how caloric restriction or caloric restriction mimetic compounds may play a role in attenuating the NLRP3 inflammasome and sterile inflammation.

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Sirt6 regulates dendritic cell differentiation, maturation, and function

Cited by 26 publications

References 39 publications

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

SIRT6 protects against endothelial dysfunction and atherosclerosis in mice

Sirtuin-1 in immunotherapy: A Janus-headed target

The role of caloric load and mitochondrial homeostasis in the regulation of the NLRP3 inflammasome

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