sirt1と膠原病
下の図にあるように
様々な様式で免疫システムの攪乱に関与している
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 , inflammation, oxidative stress , mitochondrial biogenesis , cell apoptosis , and autophagy .
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 .
Agathe et al. performed microarray experiments to identify SIRT1 as a relevant gene candidate associated with pathological angiogenesis in autoimmune arthritis mice .
The role of SIRT1 modulation on autoimmune diseases.
| Diseases | Animal models | Tissue/Cell types | Approaches | Main mechanisms and effects | |
|---|---|---|---|---|---|
| SLE | MRL/lpr mice | Kidney/ splenic CD4+ T cells | SIRT1-siRNA | SIRT1 expression was suppressed and global histone H3 and H4 acetylation levels were elevated transiently in CD4+ T cells. Serum anti-dsDNA antibody level, renal IgG deposition, and renal pathological scores, tubulointerstitial scores, decreased significantly. | |
| Pristane induced lupus BALB/c mice model | Kidney/ splenic CD4+ T cells and CD19+ B cells | Resveratrol | Proteinuria, immunoglobuin depositon in kidney, and glomerulonephritis as well as IgG1 and IgG2a in serum decreased. CD4 IFNγ+ Th1 cells and the ratio of Th1/Th2 decreased. CD69 and CD71 expression on CD4+ T cells as well as CD4+ T cell proliferation was inhibited, CD4+ T cell apoptosis increased. | ||
| SIRT1-null mice | Kidney | SIRT1 knockout | The immunoglobulin in the kidney was concentrated in the glomeruli. The frequency of anti-nuclear antibody was much higher. | ||
| RA | — | RA-FLSs | Silence of SIRT1 | FLSs proliferation and leukocytic adhesion to FLSs reduced. | |
| — | RA-FLSs | Overexpression of SIRT1 | FLSs proliferation, migration, and invasion was inhibited. RA-FLS apoptosis and caspase-3/8 activity increased. | ||
| — | Peripheral blood monocytes/ RA-FLSs | Knockdown of SIRT1 | Apoptosis of FLSs increased. IL-6 and IL-8 in FLSs reduced. Lipopolysaccharide-induced levels of TNFα in monocytes reduced. | ||
| — | RA-FLSs | Resveratrol | Phosphorylation and acetylation of p65, c-Jun, and Fos was inhibited, and expression of COX-2 reduced. | ||
| CIA mice | T cells | Resveratrol | The incidence and severity of CIA reduced. The translocation of c-Jun into the nucleus upon T cell activation was inhibited | ||
| CIA rats | Synovial tissue/ rat synovial cells | Resveratrol | Levels of cell apoptosis were enhanced. Cell proliferation was inhibited. MAPK signaling, ROS accumulation, HIF-1α-mediated angiogenesis was inhibited. | ||
| K/BxN serum transfer arthritis | Ankle tissue/ BMMs | mSIRT1 KO | IL-1, TNF-α, TRAP-positive osteoclasts, and F4/80+ macrophages in the ankles increased. Hyperacetylated p65 and increased NF-κB binding activity in BMMs, with increased M1 polarization, migration, pro-inflammatory cytokine production, and osteoclastogenesis. | ||
| CIA mice | T cells and DCs | mSIRT1 KO | The mSIRT1 KO mice exhibited less severe arthritis, which was less destructive to the joints. ROR-γT, Th1 and Th17 cells, and CD80- or CD86-positive DCs reduced. The DCs showed decreases in T-cell proliferation and the Th1/Th17 immune response. | ||
| IBD | DSS-induced colitis | Colons | Resveratrol | TNF-α, IL-6, IL-1β, IFN-γ and IL-17 increased. The expression of TIMP-3 increased and TACE was inhibited. | |
| DSS-induced colitis | Colons/ macrophages and Caco-2 cells | SRT1720 | Disease activity index, histological score, inflammatory cytokine levels, and apoptotic cell rate in colon tissues decreased. Levels of occludin and ZO-1 increased. The expression of GRP78, CHOP, cleaved caspase-12, cleaved caspase-9, and cleaved caspase-3 in Caco-2 cells and the colon tissues reduced. | ||
| Radiation-induced inflammatory bowel disease | Intestine tissues | Resveratrol | The level of bowel inflammation reduced. The activity of NLRP-3 inflammasome was inhibited. | ||
| C57BL/6 IL-10 deficient mice | Colon tissues | None | The levels of TNF-α increased and expression of SIRT1 decreased. The activation of the autophagy in mice from all stages. | ||
| Chemically-induced colitis (TNBS or oxazolone) | Inflamed IBD mucosa | Cay10591 | The activation of NF-κB and inflammatory cytokine synthesis was inhibited. | ||
| DSS-induced colitis | T cells from spleens and lymph nodes | EX-527 | Weight loss and increased iTreg formation. | ||
| MS | EAE mice | Optic nerve and RGC | Sirtinol/ SRT501 | SIRT1 activators, SRT501, significantly attenuated RGC loss in a dose-dependent manner. This neuroprotective effect was blocked by sirtinol. | |
| MHV-A59 induced MS. | Optic nerve and RGC | SRTAW04 | SIRT1 activating compounds prevent neuronal loss in viral-induced demyelinating disease involves increasing mitochondrial biogenesis with reduction of oxidative stress. | ||
| EAE mice | Optic nerve and RGC | SRT501 | Oral SRT501 prevented neuronal loss and neurological dysfunction during optic neuritis, an inflammatory optic nerve lesion in EAE. | ||
| EAE mice | Optic nerve and RGC | Resveratrol | Resveratrol prevented neuronal loss in this chronic demyelinating disease model. | ||
| EAE mice | Cerebellar tissue/ OPCs | Ex527 | SIRT1 inhibition may help to expand the endogenous pool of OPCs without affecting their differentiation. | ||
| EAE mice | Retina and optic nerves | Overexpression of SIRT1 within RGCs | SIRT1 mediated significant preservation of the OKR. SIRT1 gene augmentation was not able to suppress optic nerve inflammation or demyelination. | ||
| EAE mice | Mononuclear cells from spleen and brain, and peritoneal macrophages | Resveratrol | EAE symptoms were significantly alleviated. Resveratrol protection against EAE is not associated with declines in IL-17+ T cells but is associated with rises in IL-17+/IL-10+ T cells and CD4-IFN-γ+ and with repressed macrophage IL-6 and IL-12/23 p40 expression. | ||
| EAE mice | Spinal cords | Overexpression of SIRT1 | SIRT1 activator suppressed EAE clinical symptoms and prevented or altered the phenotype of inflammation in spinal cords. Demyelination and axonal injury were reduced. | ||
| EAE mice | NAD+ | NAD+ treatment could lessen the severity of EAE and suppress pro-inflammatory T cell responses. SIRT1 pathway was activated in the NAD+-treated. |
ROS, reactive oxygen species; HIF-1α, hypoxia-inducible factor-1α; MAPK, mitogen-activated protein kinase; NF-κB, nuclear factor-κB; mSIRT1 KO, myeloid cell-specific SIRT1 knockout; CIA, collagen-induced arthritis; DCs, dendritic cells; DSS, dextran sulfate sodium; TACE, TNF-α converting enzyme; TIMP-3, Tissue inhibitor of metalloproteinase-3; BMMs, bone marrow-derived monocytes/macrophages; ZO-1, zona occludens 1; GRP78, glucose-regulated protein 78; CHOP, CCAAT/enhancer-binding protein homologous protein; TNBS, 2,4,6-trinitrobenzenesulphonic acid; EAE, experimental autoimmune encephalomyelitis; RGC, retinal ganglion cell; OPC, oligodendrocyte progenitor cell; OKR, optokinetic response; NAD+, nicotinamide adenine dinucleotide.
Sirtuins and SIRT1
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.
2024年7月31日 | カテゴリー：関節リウマチ リウマチ外来, 膠原病 |
