Reactive oxygen species (ROS) are produced mainly during oxidative phosphorylation and by activated phagocytic cells during oxidative burst. The excessive production of ROS can damage lipids, protein, membrane and nucleic acids. They also serve as important intracellular signalling that enhances the inflammatory response. Many studies have demonstrated a role of ROS in the pathogenesis of inflammatory chronic arthropathies, such as rheumatoid arthritis. It is known that ROS can function as a second messenger to activate nuclear factor kappa-B, which orchestrates the expression of a spectrum of genes involved in the inflammatory response. Therefore, an understanding of the complex interactions between these pathways might be useful for the development of novel therapeutic strategies for rheumatoid arthritis.
Keywords: anti-oxidant enzyme, inflammation, oxidative stress, rheumatoid arthritis, ROS
Reactive oxygen species (ROS) are produced in cells by several physiological and environmental stimulations, such as infections, ultraviolet radiation and pollutants, known collectively as oxidants. Interestingly, ROS have also been considered as risk and enhancer factors for autoimmune diseases [1], as there is a significant relation between the oxidative stress and such diseases [2].
Rheumatoid arthritis (RA) is an inflammatory systemic and autoimmune disease, characterized by chronic, symmetric and erosive synovitis, mainly of peripheral joints. Most patients present rheumatoid factors, which are autoantibodies directed to the Fc fraction of immunoglobulin G, and antibodies reactive with citrullinated peptides [3,4]. RA has a prevalence of approximately 1% in the world population [5].
Rheumatoid arthritis aetiology is basically unknown, but several studies have implicated a combination of a genetic background and environmental triggers, such as infections and smoking, leading to defects in immunoregulation and a host of inflammatory mechanisms involved in joint tissue damage, including a role for oxidative stress [6].
The definition of oxidative stress as ‘a disturbance in the prooxidant-anti-oxidant balance in favour of the former’[7] implies that disturbance because of pro-oxidant conditions can be corrected by the addition of appropriate anti-oxidants. However, redox mechanisms have been shown to influence intracellular signalling, and cells seem to be very sensitive to the loss of these regulatory and control systems. These two concepts have been incorporated recently into a new definition of oxidative stress as ‘an imbalance between oxidants and anti-oxidants in favour of the oxidants, leading to a disruption of redox signalling and control and/or molecular damage’[8–10].
In this review we explore the role of oxidative stress, ROS and redox signalling in the physiopathology of RA.
Reactive oxygen species are produced during normal aerobic cell metabolism, have important physiological roles in maintaining cell redox status and are required for normal cellular functions, including cell proliferation, aggregation, chemotaxis and apoptosis, as well as regulation of intracellular signalling pathways and the activity of transcription factors, such as nuclear factor (NF)-κB, activator protein 1 and hypoxia-inducible factor-1α. ROS produced by phagocytes are critical for the protection against invading microorganisms and also seem to have important physiological roles in priming the immune system [11–13]. The functioning of T lymphocytes is influenced markedly by alterations in the intracellular redox balance. Exposure to ROS has been demonstrated to down-regulate the activity of T lymphocytes; ROS produced by phagocytes also seem to have essential physiological roles in priming the immune system as second messengers [9]. Hitchon and El-Gabalawy propose that the physiological production of ROS by phagocytes in response to antigen affects T cell–antigen interactions and possibly induces apoptosis of autoreactive arthritogenic T cells, thereby preventing autoimmune responses [14].
Phagocytic cells, such as macrophages and neutrophils, are known to be activated under oxidative conditions. This activation is mediated by the oxidase nicotinamide adenine dinucleotide phosphate (NADPH) system and results in a noticeable increment in oxygen consumption and consequent superoxide anion production O2•−) [15]. The activation of oxidase NADPH may be induced by lipopolysaccharides, lipoproteins and cytokines, such as interferon (IFN)-γ, interleukin (IL)-1β and tumour necrosis factor (TNF)-α[14–16] (see Fig. 1).
In the presence of iron ions (Fe2+) or other transition metals O2•−and hydrogen peroxide (H2O2) are converted, via the Fenton reaction, to highly reactive, aqueous soluble hydroxyl radicals (HO•), that are probably responsible for much of the cell toxicity associated with ROS [11]. As soon as HO• is formed it will react rapidly with the closest molecules, which may be lipids, proteins or DNA bases. It happens because the constant rate of hydroxyl radical reaction is very high if compared with the other reactive species (k > 109 M−1 s−1) [11].
Besides ROS, reactive nitrogen species (RNS), such as the peroxynitrite radical ONOO– generated by the reaction between O2•− and nitric oxide (NO), can also cause oxidative damage [17]. NO is a very reactive inorganic free radical, with a half-life shorter than 10 s because of its rapid oxidation to nitrites [18]. It is produced by the deaimination of L-arginine by NO synthase in the presence of NADPH and O2, producing L-citrulline and NO [17]. The addition of ONOO– to body cells, tissues and fluids leads to fast protonation, which may result in the depletion of –SH groups and other anti-oxidants, oxidation and nitration of lipids, DNA disruption, nitration and deamination of DNA bases (mainly guanine) [11].
Among the oxygen and nitrogen radicals, ONOO– can deplete –SH groupings and consequently change the redox balance in the glutathione towards oxidative stress. This unbalanced glutathione redox status induces, by redox regulation [19], the kappa-B inhibitor (IκB) kinase to phosphorylate IκB, enabling translocation of the transcription factor NF-κB to the nucleus, leading to the transcription of several inflammatory mediators (see Fig. 1).
More recently ROS have been believed to function as second messengers. Typically, second messengers are molecules generated at the time of activation of a receptor, are short-lived and act specifically on effectors to alter their activity transiently. Indeed, ROS and RNS can be generated at the time of receptor activation and are short-lived, as are other second messengers, but the specificity of their action has been more difficult to assess, except for that of NO, which binds specifically to the haem of the regulatory domain of soluble guanylate cyclase, resulting in its activation [8,20].
Despite important physiological roles, an unbalanced redox status presents potentially destructive effects on cellular biology. For this reason, several enzymatic and non-enzymatic anti-oxidant mechanisms are involved in the protection of cells and organisms in case of eventual damage caused by excessive amounts of such highly reactive mediators [17,21].
Superoxide is converted to H2O2either spontaneously or more rapidly when catalysed by the enzyme superoxide dismutase (SOD) [14]. There are three SOD isoforms: manganese-SOD resides in the mitochondria and is inducible by cytokines through the NF-κB pathway and other co-factors; copper–zinc-SOD is constitutive; and extracellular-SOD (EC-SOD or SOD3) [11].
Glutathione peroxidase (GPx) and catalase (CAT) are responsible for H2O2 degradation [15]. CAT resides in the peroxisome matrix and therefore it can degrade only the H2O2 produced in the matrix and not the H2O2 produced in the peroxisome core. H2O2 produced in the nucleus is transported to cytoplasm by tubules in the nuclear membrane, where GPx will perform the degradation [22]. The H2O2 GPx also degrades other peroxides. This is the first mitochondrial protection from H2O2 and is regulated by p53 and hypoxia [14].
Anti-oxidant mechanisms also have the participation of non-enzymatic anti-oxidants deriving from the diet, which include vitamin E, β-carotene, vitamin C and glutathione; the latter is considered the most important hydrosoluble non-enzymatic anti-oxidant, as it participates in numerous ox-reduction reactions [11,13,21]. Glutathione acts as a co-factor of GPx and other enzymes and is involved in many other metabolic processes, including the metabolism of ascorbate, communication between cells, prevention of oxidation of thiol groups of proteins and radioprotection [11].
Currently, the use of oxidative stress biomarkers can help to explore the relation between oxidative damage to macromolecules (DNA, lipids and proteins) and several diseases. Evaluation, both in vivo and ex vivo, includes measurements of DNA oxidation, lipid peroxidation and protein oxidation [23] (see Table 1).
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