Source: https://www.emjreviews.com/rheumatology/article/the-role-of-nicotinamide-adenine-dinucleotide-in-the-pathogenesis-of-rheumatoid-arthritis-potential-implications-for-treatment/
Timestamp: 2019-04-22 08:27:55+00:00

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This study was supported in part by the grants from National Natural Science Foundation of China (81701600), and the Natural Science Foundation of Zhejiang Province (LQ17H100001, LGF18H100001).
Rheumatoid arthritis (RA) is a chronic, systemic, inflammatory, autoimmune disease characterised by small joint swelling, deformity, and dysfunction. Its exact aetiology is unclear. Current treatment approaches do not control harmful autoimmune attacks or prevent irreversible damage without considerable side effects. Nicotinamide adenine dinucleotide (NAD+), an important hydrogen carrier in mitochondrial respiration and oxidative phosphorylation, is the major determinant of redox state in the cell. NAD+ metabolites act as degradation substrates for a wide range of enzymes, such as sirtuins, poly-ADP-ribose polymerases, ADP-ribosyltransferases, and CD38. The roles of NAD+ have expanded beyond its role as a coenzyme, linking cellular metabolism to inflammation signalling and immune response. The aim of this review is to illustrate the role of NAD+-related enzymes in the pathogenesis of RA and highlight the potential therapeutic role of NAD+ in RA.
Rheumatoid arthritis (RA) is an autoimmune disease characterised by synovial inflammation, synovial hyperplasia, pannus formation with subsequent joint swelling, space narrowing, and destruction of articular cartilage and bone. The exact causes of RA are still unclear. However, it is well recognised that a combination of factors, including abnormal autoimmune response, genetic susceptibility, and some environmental or biologic triggers, such as viral infection or hormonal changes, are involved in the development of RA.1 Despite the use of biological disease-modifying antirheumatic drugs, such as anti-TNF-α inhibitors, and targeted synthetic disease-modifying antirheumatic drugs, such as JAK inhibitors,2 there are still a significant number of RA patients who have poorly controlled disease. Therefore, the development of new therapies is urgently needed.
Recently, scientists found that abnormal energy metabolism is associated with the development of RA.9 During preclinical RA, when autoreactive T cells expand and immunological tolerance is broken, the main sites of disease are the secondary lymphoid tissues. Naïve CD4+ T cells from patients with RA have a defect in glycolytic flux due to the upregulation of glucose-6-phosphate dehydrogenase.3 This therefore leads to high levels of NADPH (the reduced form of nicotinamide adenine dinucleotide phosphate) and thus depleted levels of intracellular reactive oxygen species, which facilitates T cell hyperproliferation and development of proinflammatory effector functions. In clinical RA, immune cells coexist with stromal cells in the acidic milieu of the inflamed joint. This microenvironment is rich in metabolic intermediates that are released into the extracellular space to shape cell–cell communication and the functional activity of tissue-resident cells.10 However, it is still unclear how energy metabolites influence the pathogenic behaviour of T cells and regulate signalling pathways in RA.
However, the roles of NAD+ have been discovered to extend beyond its role as a coenzyme. NAD+ and its metabolites also act as degradation substrates for a wide range of enzymes, such as the Class III NAD+-dependent deacetylases (sirtuins), poly-ADP-ribose polymerases (PARP), ADP-ribosyltransferases (ART), and the cyclic ADP-ribose synthases (CD38 ectoenzymes).13,14 Through its activities, NAD+ links cellular metabolism to changes in inflammation signalling and immune response. It has been reported that NAD+ is able to promote an impressive allograft survival through a robust systemic IL-10 production, suggesting IL-10 may be a key molecule involved in NAD+-mediated immune regulation.15 Administration of NAD+ protects against experimental autoimmune encephalomyelitis (EAE) and reverses disease progression by regulating CD4+ T cell differentiation and apoptosis;16 this suggests a potential role in the pathogenesis of NAD+ and indicates potential therapeutic effects in RA by regulating the immune response. Here, the authors explore how NAD+-related substrates contribute to the progress of RA and summarise the biological effects of NAD+ in the treatment of RA.
Levels of Nam and tryptohan, the precursors of NAD+, are decreased in patients with RA.17-19 Nam has been shown to be a potent inhibitor of glucose-6-phosphate dehydrogenase, which may have benefits for conditions like RA.20 However, tryptophan has been shown to be a poor NAD+ precursor in vivo.21 NR has been found to reduce obesity-related inflammation, which may apply to other inflammatory diseases, such as RA.22 Nampt has been shown to play a major role in inflammatory arthritis because expression of Nampt is increased in both the sera and in the arthritic paw in a collagen-induced arthritis (CIA) mouse model. Furthermore, a specific competitive inhibitor of Nampt was shown to effectively reduce arthritis severity and progression of arthritis with comparable activity to the TNF inhibitor etanercept. Moreover, Nampt inhibition has been shown to reduce intracellular NAD+ concentration in inflammatory cells and circulating TNF-α level during endotoxaemia in mice.23,24 However, no papers have been published on the targeting of Nampt in human patients with RA.
Sirt1 can mediate the differentiation of inflammatory T cell subsets in an NAD+– dependent manner.34 Sirt1 is highly expressed in the thymus, suggesting the involvement of Sirt1 in T cell development. Furthermore, T cell-specific Sirt1 deletion and treatment with pharmacological Sirt1 inhibitors has been shown to suppress Th17 differentiation and exert a protective effect in a mouse model of multiple sclerosis.35 The loss of Sirt1 has been shown to compromise the survival of regulatory T (Treg) cells, resulting in antigen-induced T cell proliferation and inflammation in two mouse models.36 A deficiency of Sirt1 in mouse or human T cells has been shown to enhance IL-9 production, suggesting that Sirt1 negatively regulates Th9 cell differentiation.37 Myeloid deletion of Sirt1 impairs Th1 and Th17 cell differentiation and dendritic cell maturation in CIA.38 In contrast, Gardner et al.39 found that Sirt1 activators contribute to the suppression of T cell proliferation. Oral Sirt1 activator treatment has been shown to suppress antigen-specific T cell responses and the production of proinflammatory cytokines, including IL-6, IL-17A, and IFN-γ, in experimental autoimmune uveoretinitis mice.39 Overall, the role of Sirt1 in controlling synovitis and the differentiation of effector T cells in RA is still controversial.
ART2 could activate the cytolytic purinergic receptor in turn to affect T cell differentiation in mice. For instance, the conversion of Treg cells into Th17 cells is promoted in the presence of IL-6, primarily through the NAD+-ART2.2-P2X7 pathway. Activation of P2X7 in T cells by ATP or by NAD+-dependent ADP-ribosylation initiates a cascade of events, including the influx of calcium, the shedding of the L-selectin homing receptor, the externalisation of phosphatidylserine on the outer leaflet of the cell membrane, DNA fragmentation, and, ultimately, cell death.51,52 This mechanism is called NAD+-induced cell death.53 It has been shown that ART2.2-overexpressing mice with normal T lymphocytes are sensitive to NAD+ and prone to death. It has also been shown that the fewer B cells that express ART2.2, the lower the amount of cell death. Bannas et al.54 showed that ART2.2 transgenic T cells, but not B cells, are sensitive to NAD+-induced cell death. NAD+ can also induce apoptosis of naïve CD4+ CD62Lhigh T cells. Conversely, activated CD44high CD69high T cells are resistant to NAD+-induced cell death.55 A study has shown that CD4+ CD25+ FoxP3+ Treg cells express the ART2.2 enzyme and high levels of P2X7, and that these Treg cells can be depleted by intravenous injection of NAD+.54 This can be used to promote an antitumour immune response.54 This mechanism may provide a means by which NAD+ released during immune diseases controls T cell functions. This suggests that the NAD+-ART2.2-P2X7 signalling pathway is an important part of T cell death in mice. However, ART2 is not expressed in human T cells.
One study showed that NAD+ promotes the conversion of effector Th1 cells (CD4+ IFNγ+) into Type 1 regulatory T cells (CD4+ IL-10+ IFNγ+, Tr1) and blocks chronic inflammation independently of the cytokine milieu.16 Furthermore, after NAD+ administration, mast cells exclusively promote CD4+ T cell differentiation in vivo and in vitro, both in the absence of antigen and independently of major antigen-presenting cells. Moreover, mast cell-mediated CD4+ T cell differentiation is independent of major histocompatibility complex II and T cell receptor signalling.63 It has been reported that NAD+ promotes Treg cell conversion into Th17 cells in vitro and in vivo.15 NAD+ has been shown to promote allograft survival by promoting a robust systemic IL-10 production, which suggested that IL-10 is a key molecule involved in immune tolerance and immune regulation.15 However, Elkhal et al.15 did not consider that NAD+ is associated with apoptosis of Treg cells, which may affect the conversion of Treg into Th17. The other factor is that Treg cells are unstable in the anti-graft-dependent inflammatory state and are easily converted into Th17.17 Therefore, whether NAD+ promotes the differentiation of Treg cells towards Th17 cells and whether they directly affect Th17 cells and facilitate their differentiation remains to be further studied.
Several drugs are in development or are already available in clinics that could be useful to suppress inflammation in autoimmune diseases. Nam, a precursor of NAD+, is able to inhibit activation and modulate the activity of B lymphocytes, suggesting a potential role of this agent in regulating antibody-mediated autoimmune disorders like RA.64 There are abundant sources of Nam, NR, and NA in natural food and milk, suggesting they are generally safe.65,66 Indeed, new studies have demonstrated the therapeutic potential of supplementing NAD+ intermediates, such as NR and NMN, providing a proof of concept for the development of an effective intervention.12 NR is widely used as an NAD+ precursor vitamin. Single doses of 100, 300, and 1,000 mg of NR produced dose-dependent, safe increases in the blood NAD+ metabolome in the first clinical trial of NR pharmacokinetics in humans.67 Also, re-establishing cellular NAD+ levels with NAD+ or Nam has been shown to exert a protective effect against axonal degeneration in EAE.16,68 Restoring NAD+ levels with NR or PARP inhibitors has been shown to have a therapeutic effect on nonalcoholic steatohepatitis.69,70 Jonas et al.71 found that Nam treatment improved the global symptoms of patients with osteoarthritis, joint flexibility, and reduced inflammation when compared to placebo in patients with osteoarthritis.
NAD+ plays a crucial role in inflammatory response and autoimmune diseases through Sirts, PARP, ART, or CD38. Although most studies suggest that Sirt1 plays a proinflammatory role in the development of RA, the role of Sirt1 in synovitis and T cell differentiation remains unclear and is controversial.30,32,33,35-39 Intracellular NAD+ levels regulate tumour necrosis factor protein synthesis in a Sirt6-dependent manner.72 Sirt6 overexpression suppresses the expression of NFκB target gene in RA FLS and significantly decreases arthritis severity. Intra-articular injections of an adenovirus containing Sirt6 complementary DNA was shown to decrease arthritis severity in mice.40 This demonstrates that the NAD+-Sirt6-NFκB pathway may be an important target for the treatment of RA.
Studies have shown that ART2 is specifically expressed on T cells in mice. NAD+ can regulate murine CD4+ T cell differentiation through the NAD+-ART2.2-P2X7 signalling pathway.51-53 Due to inactivated ART2 pseudogenes in the human genome, ART2 is deficient in humans. Recently, scientists reported a higher expression level of ART1 in human CD4+ CD39+ Treg cells. ART1 participates in the resistance against cell death of Treg cells induced by NAD+.49 It is known that Treg cells are functionally defective or unstable in patients with RA and are converted to Th17 cells in the presence of proinflammatory cytokines, such as IL-6.50 ART1 may be related to the stability of Treg cells in patients with RA.
CD38 is highly expressed in synovial membranes and plasma cells from RA patients.75 The IL-1α and IL-β levels are significantly decreased after treatment with siRNA targeting CD38.59 Mice deficient in CD38 develop an attenuated collagen-induced arthritis.59,61 Inhibitors or therapeutic antibodies targeting CD38 should be tested for their ability to raise the concentration of NAD+.76,77 It is not easy to benefit from therapy through simply targeting CD38 from bench to bedside because targeting CD38 may impair the function of Treg cells and regulatory B cells.
Many studies have revealed the importance of NAD+ biosynthesis in energy metabolism and in the immune response process. It is clear that levels of NAD+ precursors, Nam and tryptophan, are decreased in patients with RA. Nam, NR, NMN, and NA are promising candidates to replenish NAD+ and reduce inflammation in patients with RA and experimental arthritis model. IL-10 may be a key molecule involved in immune tolerance and immune regulation after treatment with NAD+. Administration of NAD+ protects against autoimmune reaction and reverses disease progression by regulating CD4+ T cell differentiation and apoptosis. The authors argue that the focus of study should be moved from other diseases, like EAE, nonalcoholic steatohepatitis, or OA, to RA and the therapeutic effect of NAD+ and its precursors should be explored.
Different NAD+-consuming enzymes, such as Sirt1, Sirt6, PARP-1, ART-1, and CD38, are involved in T cell differentiation and homeostasis and synovial inflammation in RA pathogenesis. NAD+ has diverse biological functions through these consuming enzymes. Therefore, NAD+ and Sirt1/Sirt6, NAD+ and PARP-1, NAD+ and ART-1, and NAD+ and CD38 signalling pathways are more affected after NAD+ supplementation. These enzymes can be targeted to efficiently improve arthritis through inhibition of synovitis or regulation of T effector cells differentiation. Published data show that Sirt6 overexpression and PARP-1 inhibitor both have therapeutic benefits in RA animal models. In the near future, human clinical studies are needed to further confirm the therapeutic effect of NAD+ biosynthesis, especially regarding NAD+ precursors and their related consuming coenzymes in RA.
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