Autoimmune diseases (Ads) are characterized by the dysregulation of the immune system, which results in the overproduction of autoantibodies, an imbalance in tolerance to self-antigens, and immune-mediated end-organ damage (1). Multiple types of Ads seriously affect the quality of life and labour ability and impose a substantial economic and psychological burden on society and families. To date, the etiology and pathogenesis of these diseases have remained invariably unknown, and complex and diverse elements associated with the environment, genetic risk factors, mental factors, and infection, which can cause an imbalance in autoimmune processes and immunological tolerance (2–4).

Sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide (NAD⁺)-dependent histone deacetylase, has been reported to participate in regulating various biological processes, such as energetic homeostasis (5), inflammation, oxidative stress (6), mitochondrial biogenesis (7), cell apoptosis (8), and autophagy (9). There have been preclinical and clinical studies indicating the significance of SIRT1 in the pathogenesis of Ads, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), multiple sclerosis (MS), etc. In women Hashimoto’s disease patients with type 1 diabetes mellitus, SIRT1 contributed to the pathogenesis of early cardiac dysfunction (10). Agathe et al. performed microarray experiments to identify SIRT1 as a relevant gene candidate associated with pathological angiogenesis in autoimmune arthritis mice (11). The deletion of SIRT1 in endothelial promoted a proliferative, proapoptotic and activated state of endothelial cells through the acetylation of p53 and p65, and resulted in the progress of proangiogenic capacities. The deficiency of SIRT1 in endothelial cells delayed the resolution of experimental arthritis. DNA hypomethylation was the first epigenetic pattern determined in SLE patients. The overexpression of SIRT1 was found in CD4+ T cells of a murine lupus model (12), however, SIRT1-null mice showed with immunoglobulin deposition in the kidneys and a high level of serum antinuclear antibody (13). The activator of SIRT1 plays a protective role in pristane-induced lupus mice, with the alleviation of proteinuria and decreased deposition of immune globulin in the kidneys (14). SIRT1 also may represent a biomarker of relapses and a potential target for therapeutic intervention in MS (15). The decreased expression of SIRT 1 has been found to increase the levels of proinflammatory cytokines that are being involved in the pathogenesis of IBD. On the contrary, the reduced expression of SIRT1 1 maintains the gastrointestinal barrier in IBD (16).

SIRT1 is a promising candidate molecule in the treatment due to different physiological and pathological processes in Ads. In the present manuscript, we will summarize and discuss the functions of SIRT1 in Ads and the therapeutic potential of targeting SIRT1 ( Table 1 ).

Acetylation, an evolutionarily conserved posttranslational modification of lysine residues, mainly facilitates chromatin formation and gene transcription. Protein deacetylases eliminate the effect of protein acetyltransferases by removing the acetyl groups added to the lysine residues (40). These enzymes are called histone deacetylases (HDACs), which are divided into four classes in mammals (41). Class III HDACs or silent information regulator 2 (Sir2) are NAD⁺-dependent HDACs that modify histone proteins and nonhistone proteins via deacetylation (42). Sirtuins, a family of highly conserved NAD⁺-dependent HDACs, share homology with Sir2 of the yeast Saccharomyces cerevisiae and show no sequence similarity to the other HDACs (43). According to existing studies, humans have 7 sirtuin paralogues, SIRT1–7, characterized by different binding targets, tissue specificities, functions, and localization (44, 45). SIRT1, SIRT6, and SIRT7 are mainly distributed in the nucleus (46, 47). SIRT2 is mainly found in the cytoplasm. SIRT1 and SIRT2 also share nuclear-cytoplasmic shuttling (48). SIRT3, SIRT4, and SIRT5 are located in mitochondria, and SIRT3 is also expressed in the nucleus under normal conditions (49–51). SIRT1, the protein with the largest molecular mass (120 kDa) and member of the sirtuin family with the highest amino acid sequence homology with yeast SIR2 (52), has been most widely studied (53).

SIRT1, located on chromosome 10q21.3, consists of 8 introns and 11 exons. The structure of the SIRT1 protein contains 747 amino acid residues and a catalytic core region flanked by variable NH₂- and COOH-terminal domains consisting of approximately 250 amino acids (54). The variety of terminal domains is associated with the diversity of sirtuin functions. This domain forms the hairpin structure that compliments with the β sheet of the NAD⁺-binding domain, and the NH₂-terminal domain potentiates the catalytic activity (55). In addition, extensions of the NH₂- and COOH-termini influence the functions of SIRT1, which are the targets of posttranslational modifications (56). Through the action of NAD⁺, SIRT1 removes the acetyl moieties of ϵ-acetyl-lysine residues of histones and other target proteins, thereby producing 2’-O-acetyl-ADP-ribose, nicotinamide, and the deacetylated substrate (57, 58). SIRT1 not only deacetylates lysine residues of histones, such as lysine 16 of H4, lysine 26 of H1, and lysine 9 of H3, but also regulates the activity of a number of transcription factors via deacetylation (59). SIRT1 epigenetically silences these target proteins at the transcriptional or posttranslational level, such as forkhead box class O (FoxOs), p53, nuclear factor-κB (NF-κB), nuclear factor E2-related factor 2 (Nrf2), HIF1α, AMP-activated protein kinase (AMPK), β-catenin, mitochondrial peroxisome proliferator-activated receptor γ coactivator 1 alpha (PCG-1α), proliferator-activated receptor gamma (PPARγ), and Notch. SIRT1 participates in a series of pathological and physiological processes, including cell metabolism and DNA repair. The regulation of diverse physiological signalling pathways and targets by SIRT1 makes it a promising therapeutic target. However, the specific mechanism of SIRT1 in Ads is unknown.

Due to continuous exposure to a variety of pathogenic agents, such as bacteria, viruses, and fungi, the body defends against these potentially fatal infections through a series of highly regulated responses known as innate and adaptive immunity. The targets of SIRT1 can affect immune cells and immune responses to modulate the progression of chronic autoimmune and inflammatory diseases ( Table 2 ).

Circulating monocytes from the blood enter the tissue and then develop into macrophages after differentiation and maturation. These phagocytes affect the immunopathogenesis of Ads. In SIRT1-deficient macrophages, hyperacetylation of NF-κB p65 results in increased levels of proinflammatory cytokines, such as tumour necrosis factor (TNF)-α and interleukin (IL)-1β, compared to the control (60). Furthermore, mice lacking SIRT1 in macrophages have high levels of activated macrophages in the liver and adipose tissues, which promote insulin resistance and metabolic syndrome. Clearly, p50/p65 is located in the cytoplasm mainly through an interaction with the inhibitor protein κB (IκB), and the activation of macrophages causes the degeneration of IκB, transferring NF-kB to the nucleus and finally promoting the expression of inflammatory genes (74). In RAW264.7 macrophages, siRNA-mediated knockdown of SIRT1 increased the expression of activated NF-κB and inflammatory factors and cytokines (61). Imperatore et al. reported an essential role for SIRT1 in the self-renewal of macrophages through the regulation of the cell cycle and longevity pathways (62). Overexpression of SIRT1 in bone marrow-derived macrophages increases their proliferative capacity. Silencing and deleting the SIRT1 gene restricts the self-renewal of macrophages. Moreover, SIRT1 inhibition negatively regulates the G1/S transition, cell cycle progression, and renewal, which are associated with the inhibition of E2F1 and Myc and the activation of FoxO1. Activator protein-1 (AP-1), which is composed of c-Fos and c-Jun, is also regulated by SIRT1 to affect inflammatory gene transcription. SIRT1 binds to c-Fos and c-Jun and deacetylates c-Jun, thereby inhibiting the transcriptional activity of AP-1 in peritoneal macrophages and reducing AP-1-associated expression of inflammatory mediators, including cyclooxygenase-2 (COX2) and prostaglandin E2 (63).

Dendritic cells (DCs) play a key protective role in promoting antigen-specific responses by adaptive immune cells and in producing a variety of chemokines and cytokines that recruit immune cells into the target tissues following the invasion of pathogenic microorganisms (75). SIRT1 regulates the generation of cytokines, such as IL-12 and TGFβ-1, by DCs through HIF1α modulation, which potentially regulates the formation of helper T (Th)-1 cells and regulatory T cells (Tregs) and the function of DCs (64, 76). The inhibition of SIRT1 in DCs promotes the differentiation of Th1 cells while restricting the differentiation of Tregs. In a mouse colitis model, transferring naïve CD4⁺ T cells into mice with DCs with a specific deletion of SIRT1 aggravated colonic inflammation and promoted weight loss. In cocultures of activated DCs with CD4⁺ T cells, pharmacological SIRT1 inhibition increases the Th1/Treg ratio and the expression of IFN-γ and IL-12 and reduces the expression of TGFβ1 (77). In a mouse asthma model, pharmacological inhibition of SIRT1 increases the activity of PPARγ and inhibits Th2 cell responses in allergic airway inflammation, which are associated with an imbalance in the maturation and migration of lung DCs (65). The loss of SIRT1 limits DC transfer into the draining lymph nodes, leading to disrupted Th2 cell differentiation. In a mouse OVA-induced airway inflammation model with DC-specific deletion of SIRT1 (66), the maturation and migration of DCs are reduced. Coculture of activated SIRT1-deficient DCs with CD4⁺ T cells inhibits the differentiation of Th17 cells, which is reversed by anti-IL-27 and anti-IFN-β antibodies. In respiratory syncytial virus infection, SIRT1 promotes the activation of DCs to produce efficient antiviral immune responses (78).

The role of SIRT1 in the adaptive immune response was mainly identified to be a negative regulator of T cell function. The levels of SIRT1 are increased in activated T cells and anergic T cells compared to mature naïve T cells (67). Compared with wild-type littermates, CD4⁺ T cells from SIRT1-deficient mice appear to exhibit greater proliferation and cytokine production (67). However, mice with a SIRT1 deletion do not present abnormal T or B cells, suggesting that SIRT1 is unlikely to be a key factor contributing to the activation of T or B cells. SIRT1 deficiency is still an important factor associated with a higher risk of Ads (79).

The hyperactivation of T cells with a specific deletion of SIRT1 is likely to be associated with the loss of inhibition of NF-κB and AP-1 activity. SIRT1 inhibits the AP-1 signalling pathway mainly through the deacetylation of c-Jun, thereby inhibiting T cell activation and proliferation. In addition to directly regulating the activity of transcription factors, SIRT1 regulates related genes that affect T cell proliferation and function. Bclaf1, initially identified as a Bcl-2-binding protein, is considered required for T cell activation (80). SIRT1 is a suppressor of Bclaf1 transcription that inhibits the activity of NF-κB and deacetylates histone lysine residues. The differences in Bclaf1 levels and Bclaf1 locus histone deacetylation between wild-type animals and mice with systemic knockout of SIRT1 are not significant in naïve, un-activated T cells (81). In the presence of IL-6, IL-23, and TGFβ, naïve T cells cultured with antigen-presenting cells induce the generation of Th17 cells, which have been proven to participate in the immunopathogenesis of certain Ads (68). SIRT1 is expressed at high levels in Th17 cells and plays an essential role in Th17 cell formation. SIRT1 binds to and deacetylates the transcription factor retinoid acid receptor-related orphan receptor gamma (RORγt), promoting the differentiation of Th17 cells by activating IL-17 and repressing the IL-2 promoter (82). Mice with a targeted deletion of SIRT1 in T cells showed a reduction in Th17 differentiation through the suppression of IL-17 expression and induction of IL-2 expression. Additionally, SIRT1 also limits Th17 differentiation by deacetylating signal transducer and activator of transcription (STAT)-3, which is required for RORγt transcription (69). Several studies found that increasing rather than suppressing SIRT1 may inhibit Th17 differentiation (70, 83). More evidence is needed to prove the direct effect of SIRT1 on Th17 development. SIRT1 also functions as a negative regulator in the differentiation of IL-9-secreting effector cells and Th9 effector cells, which have been shown to possess antitumour and antiallergic activities (84). Targeted deletion of SIRT1 in mouse CD4⁺ T cells or silencing of SIRT1 in mouse or human T cells promotes the differentiation of Th9 cells and IL-9 production, whereas ectopic expression of SIRT1 inhibits IL-9 production and Th9 differentiation (85). Additionally, IL-9 produced by SIRT1-deficient T cells protects against tumours and increases the levels of allergic pulmonary inflammation.

IL-2 plays an important role in the proliferation of activated T cells and in preventing their apoptosis induced by the high-affinity IL-2 receptor CD25 through the phosphoinositide-3- kinase (PI3K)/Akt pathway to suppress FoxO1, 3, and 4 (71). SIRT1 is a very important deacetylase of FoxO family members. Normally, SIRT1 is likely to regulate the activation of T cells via the deacetylation of FoxO proteins and the inhibition of FoxO apoptotic signalling and the IL-2 signalling pathway.

SIRT1 regulates the acetylation and stability of FoxP3, a crucial transcription factor involved in the differentiation of Tregs (86). Hyperacetylation of FoxP3 diminishes its polyubiquitination and increases its stability. The inhibition of sirtuins downregulates the acetylation of FoxP3 and promotes the ubiquitination and degeneration of FoxP3. In addition, the Notch receptor in Tregs plays an essential role in the survival of Tregs and is associated with the antiapoptotic effect of the Notch1 intracellular domain. SIRT1 was shown to stabilize the Notch1 intracellular domain proximal to the membrane to promote Treg survival (87). However, in contrast, SIRT1 inhibition promotes the formation of FoxP3⁺ Tregs with elevated immunosuppressive activity (88). Beier et al. reported that conventional CD4⁺FoxP3^- T cell-specific deletion of SIRT1 in mice rarely affected the numbers of T cells and their activation and proliferation but increased the expression of FoxP3 and suppressive activity of Tregs in vitro and in vivo (72). Compared to wild-type mice, mice with specific deletions of SIRT1 in FoxP3⁺ Tregs survived significantly longer with mismatched heart allografts. Wild-type mice treated with SIRT1 selective inhibitors (splitomicin and EX-527) showed similar results. Another study reported that mice with a SIRT1 deletion and mismatched renal allografts experienced longer survival than wild-type mice (89). CD4⁺ T cells isolated from a cervical heterotopic heart transplantation mouse model treated with sirtinol (sirtuin inhibitor) showed significantly lower expression of IL-17A and RORγt and higher expression of FoxP3 (90). In vivo, sirtinol reduces the differentiation of Th17 cells and increases the proportion of Treg cells among splenocytes. Additionally, co-transfection of SIRT1 with FoxP3 increases FoxP3 proteasomal degeneration, while SIRT1 inhibition increases FOXP3 transcriptional activity in human Treg (91). SIRT1 inhibition might increase FoxP3 acetylation to promote the production and functions of FoxP3⁺ Tregs and inhibit the acetylation of RORγt and the differentiation of Th17 cells, thereby affecting the Th17/Treg ratio (92, 93). Nonetheless, SIRT1^-/- mice develop spontaneous and severe Ads (67) but not mice with SIRT1-deficient CD4⁺ T cells. A potential explanation for this finding is alterations in thymic T cell selection in SIRT1^-/- mice and the expression of autoimmune regulator (AIRE), which is required for the former. SIRT1 also plays a key role in regulating the expression of AIRE (79).

The function of SIRT1 in another group of lymphocytes has rarely been studied. SIRT1 regulates the activation of B cells through CD38 and NAD (94). In another study, SIRT1 regulated antibody maturation in B cells (95). The activation of B cells resulted in the inhibition of SIRT1 and the upregulation of activation-induced cytidine deaminase (AICDA). B cells obtained from mice with B cell-specific deletion of SIRT1 showed reduced deacetylation in activated B cells, increased AICDA levels, and the induction of antibody maturation. More studies are needed to clarify the role of SIRT1 in the activation and differentiation of B cells.

In recent years, the function of SIRT1 has expanded far beyond its initial impression as a prominent NAD⁺-dependent class III HDAC of the sirtuin family. SIRT1 participates in the complex coordination of the immune system and Ads. Although various articles have examined the roles of SIRT1 in suppressing the promotion of autoimmune diseases, many studies described in this review support the hypothesis that SIRT1 represents a possible biomarker of relapses and a potential target for therapeutic intervention in multiple Ads, including SLE, RA, IBD, MS, regardless of whether it functions as an activator or inhibitor. SIRT1 regulates the expression and activity of some transcription factors and genes, affecting immune cell activation, differentiation, and function.

SIRT1 not only affects histones deacetylation, but also deacetylation of various transcription factors, including p65, p53, FoxO family, STAT3, PGC1α, and PPARγ, leading to transcription repression. SIRT1 regulates the activity of p53 and FoxO3 through deacetylation and promotes cell survival via suppression of apoptosis and cell death in response to DNA damage and oxidative stress. The deficiency of SIRT1-mediated deacetylation of FoxO3a causes increased etoposide-induced apoptosis. On bone tissues, SIRT1 maintains its “self-renewal” ability through the inhibition of inflammation, oxidative stress, and senescence. SIRT1 also exerts anti-inflammatory effects through the inhibition of NF-kB, AP-1, and STAT3 pathways. SIRT1 causes the deacetylation and inactivation of STAT3 during caloric restriction. SIRT1 inhibits the NF-kB pathway through deacetylation of p65 and regulates cellular response to hypoxia via deacetylation of HIF-1α. However, loss of SIRT1 might lead to improved immune surveillance against pathogenic infection and nonself antigens, not all diseases benefit from the activation of SIRT1 or might even worsen Th2-mediated immune responses. All these highlight an important transcription modulatory function by SIRT1 activity, and the essential roles of SIRT1 in different Ads and different stages of the disease.

Although substantial progress has been achieved, the study of SIRT1 functions in the immune response is still in the early stage ( Figure 1 ). In future studies, experiments are designed to understand how SIRT1 affects different cell types in a coordinated manner within the immune system and the different roles of SIRT1 in different subsets of T cells, B cells, and dendritic cells will be valuable. The precise function of SIRT1 in the development of Ads remains unclear, and future studies are also required to elucidate the molecular pathways and targets regulated by SIRT1 and their roles in treating Ads, which can be used to design precise and more efficient therapies with limited detrimental or unwanted effects. However, new models, methods, and techniques for investigating SIRT1 must be developed to promote its clinical application.

PS and XD wrote the first draft of the manuscript. All authors participated in manuscript revision and have approved the submitted version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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