Myeloid Deletion of SIRT1 Induces Inflammatory Signaling in Response to Environmental Stress

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-B 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-B 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-B-mediated transcription, implying that myeloid cell-specific modulation of this sirtuin may be beneficial in the treatment of inflammation and its associated diseases.Chronic inflammation is increasingly recognized as a causal factor leading to the development of obesity, insulin resistance, and type 2 diabetes (15, 31). This low-grade inflammatory state is in part mediated by macrophages, key sentinels of the innate immune system. Macrophages quiescently monitor the tissue milieu for signs of infection or damage (13,25). Upon stimulation, macrophages infiltrate resident tissue, perpetuating local inflammation and contributing to the development of insulin resistance and metabolic derangements (17,37,43). The nuclear factor kappa B (NF-B) transcription factor signaling pathway is a key mediator of immune response in macrophages (5, 7). NF-B is composed of a heterodimer of p50 and RelA/ p65 subunits. In unstimulated cells, NF-B resides in the cytoplasm bound to its inhibitory proteins, which are members of the inhibitor of B (IB) family. Stimulation of cells by environmental factors, including dietary fatty acids, liberates NF-B, allowing it to translocate to the nucleus, where it mediates gene transcription (12). Under environmental stresses, such as those surrounding obesity-like conditions, this chain of events is believed to ultimately lead to insulin resistance, setting in motion the vicious cycle of the metabolic syndrome.Sirtuins are highly conserved NAD ϩ -dependent deacetylases that target histones, transcription factors, coregulators, and other key regulators to adapt gene expression and metabolism to the cellular energy state (16,22,32). SIRT1, the leading family member, has been reported to promote longevity in species ranging from yeast to flies (1)(2)(3)6). It is believed that these life-exte...

Succinate: a metabolic signal in inflammation

“…NLRP3 associates with the acetylated a-tubulin and localizes to the mitochondria where it is activated in a ROS-dependent manner. Finally, Sirt6 has been demonstrated to deacetylate the promoter of specific NF-kB target genes including interleukin 1b (IL-1b), thereby limiting NF-kB accessibility to these promoters and decreasing transcription [21].…”

Sirtuins and inflammation: Friends or foes?

“…Collectively these data suggest a complex regulatory role for SIRT6 in controlling an inflammatory response, since this sirtuin member could inhibit selected NFkB target genes at the transcriptional level, while increasing the translation of other cytokine mRNAs by a yet to be defined mechanism (Figure 2). Note however that TNF gene transcription does not appear to be affected by siRNA-mediated SIRT6 downregulation [29], suggesting that SIRT6 may in fact specifically promote TNF translation, while inhibiting IL-1 gene transcription in the same cells. Collectively, these observations suggest that sirtuins, and in particular SIRT6, may affect the cytokine profile of activated immune cells in a subtle fashion, by acting at distinct steps of the synthetic process.…”

“…Thus, while SIRT1 inhibits NFkB activity by direct posttranslational modification of p65, SIRT6 acts by decreasing promoter accessibility to p65 (Figure 2). Notably, a compensatory role for SIRT6 has been recently demonstrated in SIRT1-deficient macrophages [29]. In these cells, SIRT6 was found to be strongly associated with selected NFkB promoters following TNF stimulation, thus attenuating the increased NFkB activity caused by the loss of SIRT1.…”

“…However, it must be noted that Guarente's team has observed an opposite outcome in a similar model of liver-specific SIRT1 deletion, with SIRT1 absence proving to have a beneficial effect on several metabolic parameters following HFD, even if no effect on NFkB acetylation or liver inflammation was reported [30]. The increase in F4.80 expression in Purushotham's study suggests an important macrophage infiltration and this prompted the authors to disrupt SIRT1 in macrophages and assess the consequences of HFD feeding [29].…”

“…A similar question has been elegantly addressed by Li's team, who focused on SIRT1's role in maintaining liver homeostasis. In two successive papers, Li's team has knocked out SIRT1 expression in hepatocytes [28] and in macrophages [29], and has assessed how this would affect liver steatosis following a HFD. Purushotham's liver specific SIRT1-KO mice (LKO) have impaired lipid homeostasis and are more prone to developing liver steatosis when fed a HFD, as compared to wt littermates [28] .…”