Psoriasis is a chronic non-infectious skin disease with unclear etiology and lack of sufficiently effective therapy [1]. Psoriasis is a global health problem. There are more than 100 million people in the world affected by this disease [1]. Psoriasis is characterized by an unpredictable course of the disease, as well as a high likelihood of developing a number of serious comorbidities including arthritis, Crohn’s disease, ulcerative colitis, cardiovascular disease, metabolic syndrome, and depression [1]. Psoriasis has an autoimmune nature, its key feature is the occurrence of stable inflammatory response as a result of increased infiltration of immune cells, which, in turn, leads to increased and uncontrolled proliferation of keratinocytes, which make up to 90% of epidermal cells, present from the basal to the stratum corneum, and are the primary protection of the skin from external factors [2]. The pathogenesis of psoriasis is very complex and is based on the intercellular interaction between keratinocytes, leukocytes, and other types of resident skin cells [2]. At the same time, keratinocytes play an important role both in the initial phase, accelerating inflammation, and during the maintenance phase, contributing to the development of a chronic inflammatory response [3]. The etiology of psoriasis is not completely clear, but includes both hereditary and non-hereditary factors. To date, numerous loci associated with predisposition to psoriasis have been identified, among which PSORS1 locus located on chromosome 6p21 plays the greatest role in predicting the development of this disease [4]. Non-hereditary factors include sunburn, trauma, various infectious diseases, alcohol and tobacco consumption, certain medications, and obesity [4]. Currently, there are no therapeutic agents that can completely cure psoriasis [5]. However, there are drugs that alleviate the condition of patients with psoriasis. The first line of defense for the treatment of mild to moderate psoriasis is the use of topical therapies, among which ointments and creams based on corticosteroids are most commonly used [5]. Phototherapy can also be used to treat moderate and severe psoriasis, which consists in exposing the skin to a certain dose of natural or artificial radiation [6]. For the treatment of moderate and severe psoriasis in the absence of a positive reaction to other drugs, injectable systemic drugs based on steroid hormones, retinoids, cytostatics, as well as biologics are used [6]. Each drug has side effects and should be used with caution, especially systemic drugs, for example, a known side effect of the cytostatic methotrexate is hepatotoxicity [7], for cyclosporine severe side effects include nephrotoxicity and myelosuppression [8] and for monoclonal antibodies immunosuppression may occur, which increases the risk of infection [6]. The existing imperfections of current therapeutic strategies make us think about new options for the treatment of psoriasis, which could level out the key targets of pathological foci of the disease and, thus, stop or even completely cure psoriasis. In this review, we propose to consider oxidative stress (OS), one of the significant pathological conditions of the cell, as a basis for the search for new therapeutic targets for psoriasis.

Reactive oxygen species (ROS) are important cell signaling molecules, which, however, at high concentrations can cause severe damage to biological macromolecules and lead to the development of a pathological condition known as OS [9]. OS plays an important role in the pathogenesis of various chronic diseases [10], including psoriasis, which will be discussed in more detail below. At acceptable concentrations, ROS perform an antimicrobial function and is involved in the activation of various important signaling pathways, including cell proliferation and differentiation, induction of apoptosis, and regulation of autophagy [9]. The main types of ROS include superoxide anion radical (O${}_2$${}^{.}$${}^{-}$) and hydrogen peroxide (H${}_2$O${}_2$). As a result of the damaging effect of ROS on biological macromolecules, secondary radicals arise that also have oxidative activity, such as 4-hydroxynonenal and peroxynitrite, which lead to the formation of a chain reaction [11]. The main sources of ROS in the cell are mitochondria and NADPH oxidase, an enzyme located predominantly on the plasma membrane of macrophages and catalyzing the formation of NADP${}^{+}$ from NADPH with the formation of extracellular O${}_2$${}^{.}$${}^{-}$, which is involved in antimicrobial defense and can act as a signaling molecule, regulating some biological processes including apoptosis, and senescence [11]. In mitochondria, ROS is generated as a by-product in the course of electron transport chain (ETC) reactions occurring on the inner mitochondrial membrane, the final result of which is the formation of macroergic ATP molecules. In mitochondria, ROS are formed as O${}_2$${}^{.}$${}^{-}$, which is then converted into H${}_2$O${}_2$ and other oxidative molecules [12]. In the Electron transport chain (ETC), the main sources of O${}_2$${}^{.}$${}^{-}$ are complex I, from where ROS are transported to the mitochondrial matrix, and complex III, which produces O${}_2$${}^{.}$${}^{-}$ in addition to the matrix into the intermembrane space [12]. Due to the constant generation of O${}_2$${}^{.}$${}^{-}$ in mitochondria, there is an antioxidant defense system represented by enzymes that convert highly reactive radicals into neutral molecules. The best-known antioxidant enzymes are glutathione peroxidase (GSH-Px), superoxide dismutase (SOD), and thioredoxin peroxidase [13]. Cellular sources of ROS also include peroxisomes, which perform a large number of metabolic functions:$\beta$-oxidation and $\alpha$-oxidation of fatty acids, metabolism of purines, amino acids. During the reactions taking place in peroxisomes, various ROS and RNS (reactive nitrogen species) are synthesized: O${}_2$, H${}_2$O${}_2$, hydroxyl radical (OH•), peroxynitrite (ONOO${}^{-}$ ), and nitric oxide (NO) [14]. The main enzymes that catalyze the reactions leading to the formation of ROS in peroxisomes are xanthine oxidoreductase and urate oxidase [14]. Like mitochondria, peroxisomes also have an antioxidant defense system [15]. Thus, ROS are predominantly formed as a by-product during metabolic reactions, so there are also systems in the immediate vicinity that inactivate the oxidative action of ROS. When OS occurs, the antioxidative defense systems are exhausted or they themselves initially undergo dysfunction, as a result of which they cannot adequately resist the spread of OS.

OS occurs as a result of an imbalance between the production of ROS and the functioning of the antioxidant system. A decrease in the antioxidant capacity of the cell may result from a decrease in the activity of enzymes of the antioxidant system, including (SOD), catalase (CAT), and(GSH-Px), as well as a decrease in the concentration of compounds that have an antioxidant effect, both endogenous (glutathione (GSH)) and exogenous (carotenoids, tocopherols) [16]. In a mouse model, it was shown that genetic knockout of extracellular SOD led to IL-23-mediated skin inflammation, which was determined by increased accumulation of immune cells: CD4${}^{+}$ T-lymphocytes, CD11b${}^{+}$ macrophages, and CD11c${}^{+}$ dendritic cells, as well as high production of pro-inflammatory cytokines [17]. And in people with psoriasis, there is a decrease in the level of a-tocopherol [18]. Increased ROS production leading to OS in psoriasis can be caused by external factors, primarily ultraviolet radiation [16]. Also, an increase in ROS production may be associated with exposure to toxic substances and their metabolites [19]. It should be taken into account that the described OS inducers are possible factors that increase the risk of developing psoriasis, but they can also cause OS in healthy people who are not predisposed to this type of disease. In addition, it was found that OS affected the formation of a damaged stratum corneum, which was important in the pathogenesis of psoriasis [20]. The development of OS in keratinocytes affects the triggering of the inflammatory response through the impact on several signaling pathways, such as: NF-$\kappa$B, MAPK and STAT3, which leads to the production of pro-inflammatory cytokines [21]. In a state of OS, keratinocytes release nucleotides and antimicrobial peptides, which contribute to the recruitment of dendritic cells [22]. The described events are initiating steps in the development of an autoimmune reaction in psoriasis. Special attention deserves the ability of ROS to influence lipid metabolism in psoriasis, which causes the formation of products of lipid peroxidation, including oxidized low-density lipoproteins (LDL) [23]. Increased accumulation of LDL leads to the activation of phospholipase A2, whose action is associated with the formation of metabolites of arachidonic acid. However, the most important point is the activation of cGMP during the process of lipid peroxidation with a simultaneous decrease in the level of cAMP, which leads to increased epidermal proliferation observed in patients with psoriasis [24].

The main symptom of autoimmune diseases, including psoriasis, is the destruction of the organism’s own intact tissues by the immune system as a result of impaired antigen recognition, during which autoantigens are recognized as foreign. Both innate and adaptive immune cells are involved in the development of an autoimmune reaction in psoriasis [16]. Under conditions of increased OS, keratinocytes begin to secrete proteins into the extracellular space, which are recognized by immune cells as autoantigens. The characterized autoantigens in psoriasis are proteins: LL-37, ADAMTSL5, PLA2G4D, and keratin 17 [25]. Dendritic cells are a key population of immune cells responsible for the development of the autoimmune response in psoriasis. The autoantigens taken up by dendritic cells are fragmented and exposed to the surface of the cell membrane as part of the MHC, which leads to antigen presentation to T-cells. OS also contributes at this stage of psoriasis pathogenesis, since ROS are stimulators of antigen presentation by dendritic cells [26]. Skin dendritic cells are represented by epidermal dendritic cells (called Langerhans cells) and dermal dendritic cells (myeloid and plasmacytoid) [27]. The main pathological population of dendritic cells in psoriasis is myeloid CD11c${}^{+}$ BDCA-1${}^{-}$ dermal dendritic cells, the concentration of which is greatly reduced as a result of effective therapy in psoriasis [28]. The imbalance of redox condition in psoriasis is observed systemically, and not only in keratinocytes, which provides additional stimulation to the immune system, primarily by increasing the production of pro-inflammatory cytokines. Thus, through the production of TNF-$\alpha$ and IFN$\gamma$ by dendritic cells, ROS initiate the proliferation and differentiation of T-helpers, the main populations of which in psoriasis are Th17, Th1 and Th22, which in turn produce such pro-inflammatory cytokines as: IL-17, IL -23, TNF-$\alpha$, IL-22, IL-26 and IL-29 [16]. The key regulator among them is IL23, which acts on T-cells to increase IL-17 expression and also stimulates natural killer cells and neutrophil production of IL-17, which is the key player in the pathogenesis of psoriasis [16]. The pro-inflammatory cytokines contribute to increased proliferation of keratinocytes, which leads to the development of epidermal hyperplasia, which is one of the significant manifestations in patients with psoriasis [29]. Neutrophils also play a noticeable role in psoriasis, one of the characteristic features of which is the formation of neutrophil extracellular traps (NETs). And if, with infectious diseases, NETs play a positive role, being real savory traps against pathogens, whereas in the case of autoimmune diseases, NETs formation can aggravate the inflammatory state and tissue damage [30]. Some of inflammatory factors are the initiators of NETosis, during which a large amount of ROS is produced, additionally enhancing inflammation. At the same time, ROS play the role of agents which are feedback amplifiers relative to neutrophils: increased ROS levels released together with NETs activate the production of CXCL1/2 and CXCL8 by keratinocytes, which enhance the recruiting of neutrophils into the outbreak of autoimmune inflammation [31]. Schematically, the development of autoimmune response in psoriasis is presented in Fig. 1.

Fig. 1.

Two ways of immune cells involvement in the development of psoriasis.

Keratinocytes are cells inducing an autoimmune reaction for psoriasis. In this case, the inducing effect of keratinocytes can be divided into 2 branches. The first is connected with the products of pro -inflammatory cytokines, which lead to the involvement of various leukocytes, such as: macrophages, neutrophils, dendritic cells, lymphocytes and further development with their participation of self -sustaining inflammation. The second branch is associated with the release of autoantigens, which are captured and processed by dendritic cells and are presented on their surface with T-lymphocytes, which cause an adaptive response, in which in psoriasis development Th1, Th17 and Th22 lymphocytes play the major role. At the same time, ROS directly affect the initiation and strengthening of autoimmune processes at each stage of the development of the disease.

Keratinocytes play a direct role in the intensification and subsequent development of the chronic phase of inflammation. As a result of exposure to pro-inflammatory cytokines, keratinocytes, in addition to high proliferative activity, acquire the ability to produce high levels of cytokines, such as: CXCL1/2/3, CXCL8, CCL2 and CCL20, which lead to increased recruitment of leukocytes involved in autoimmune inflammation, including: dendritic cells, macrophages, neutrophils, and Th17 lymphocytes [3]. In addition, keratinocytes secrete antimicrobial peptides, such as S100A7/8/9/12, hBD2 and LL37, which contribute to additional stimulation of the innate immune system and increased inflammation [3]. Keratinocytes produce new portions of ROS, which act as strong chemoattractants for neutrophils, promoting their invasion and accumulation in skin psoriatic lesions [32]. Neutrophils, like other immune cells in the inflammatory focus, in turn release high levels of ROS, which lead to an even greater increase in OS and the development of the chain reaction of increased inflammation, which eventually develops into a state of chronic inflammation. The general scheme of the pathogenesis of psoriasis based on the effects of ROS is shown in Fig. 2.

Fig. 2.

General scheme of psoriasis pathogenesis based on ROS effects.

External factors (for example, UV) cause an increase in ROS production in keratinocytes and a weakening of antioxidant protection, which initiates OS, epidermal proliferation,the development of inflammation, which subsequently involves leukocytes and autoantigens released by keratinocytes resulting in an autoimmune reaction onset that becomes chronic, enhancing total inflammatory immune response.

OS is an important factor in the pathogenesis of psoriasis, on the basis of which tools for the diagnosis and therapy of this disease can be developed, as shown in the previous sections. Nevertheless, several important questions remain, the answers to which will help shed light on the further fight against psoriasis, as well as other chronic autoimmune diseases. First of all, an important step is the search for new biomarkers of OS, which can be effectively used as useful tools for differential diagnosis of psoriasis, OS as was shown in the example of 8-OHdG. It is also important to differentiate the quantitative values of the biomarkers content depending on the severity of psoriasis. The creation of these test systems will contribute to more accurate prognosis of the disease, as well as a more informed prescription of therapy, which will help to avoid “unnecessary” side drug effects. It should be noted that the biomarkers presented in this review were selected based on the criterion of a high probability of introduction into clinical practice based on the available studies in our opinion, however, this choice is subjective and does not mean that other compounds are less promising (see review [76]). It is also worth pointing out that despite the fact that the considered biomarkers of OS can be used to diagnose psoriasis, none of them is the specific marker of psoriasis, so they cannot be used as the only tool for diagnosing psoriasis. With regard to antioxidant therapy, it makes sense to understand which combinations of antioxidants and traditionally used drugs provide the best therapeutic effect in the treatment of psoriasis. The use of antioxidant monotherapy currently does not seem appropriate, as stated in the previous section. An important direction is the search for compounds capable of restoring the natural antioxidant function of cells. In this regard, the question arises: what factors are predominant in the occurrence of OS in psoriasis (external, including exposure to ultraviolet radiation, or internal, associated with a decrease in the activity of antioxidant enzymes)? In the context of the described studies, a promising strategy may be to search for compounds with theragnostic properties, which will allow combining efforts to develop new drugs and diagnostic tests. Also an important direction in the treatment of psoriasis is the search for new therapeutic targets that play a significant effect in the pathogenesis of this disease. An example of these targets is the transcription factor NRF2, the exact mechanism of which in the context of psoriasis requires a thorough study. On the one hand, the NRF2 activates the genes of an antioxidant response (ARE) [77], on the other hand, it triggers the proliferation of keratinocytes in psoriasis [78]. Another issue requiring attention is the degree of development of OS in different types of immune cells, which may allow the identification of new subtypes of leukocytes that play a key role in the pathogenesis of psoriasis. It is also worth paying attention to additional factors that initiate excessive proliferation of keratinocytes, for example, a shift in the prevailing metabolic pathways. In this regard, it is important to consider the relationship between OS and the work of mitochondria under these conditions, as well as to identify the possibility of developing mitochondrial dysfunction and its effect on metabolic changes. This strategy could potentially lead to the discovery of new therapeutic targets in the treatment of psoriasis. So, in the study [79], a change in the content of some metabolites was revealed, as well as the modulation of the main metabolic pathways in response to OS in the skin. So, an increase in the pentose phosphate pathway and $\beta$-oxidation of fatty acids and the weakening of the Krebs cycle was noted. The important step in this direction is the development of diagnostic tests to assess oxidative stress directly in damaged tissues of the body. The measurement of oxidative stress markers in biological fluids can often inaccurately correlate with the actual levels of damage and inflammation, since the concentrations of biomarkers in these cases primarily characterize the rate of their formation and excretion. Determination of biomarkers of oxidative damage can give accurate results not only in in vivo tests, which can be difficult to implement, but also in biopsy specimens, since, unlike ROS themselves, they have a longer half-life.

OS is a detectable phenomenon in cells for various chronic diseases; its development is based on an increase in the concentration of ROS, which shifts the redox balance in cells and leads to a stress state. In psoriasis, ROS are important participants in all stages of pathogenesis, from the initial triggering of OS in keratinocytes to the development of a chronic inflammatory response. Various compounds can be used as markers of OS in psoriasis, while the detection signal indicating the onset of pathology can manifest itself in various ways: an increase in concentration, a decrease in concentration, and also the transformation of the marker into another compound. Several antioxidants are potentially being considered as potential therapies for psoriasis in combination with drugs that have proven efficacy. The use of antioxidants as monotherapeutic agents is unlikely to provide the desired therapeutic effect.

ROS, reactive oxygen species; OS, oxidative stress; ETC, electron transport chain; SOD, superoxide dismutase; RNS, reactive nitrogen species; CAT, catalase; GSH, glutathione; LDL, low-density lipoproteins; HDL, high-density lipoproteins; MHC, major histocompatibility complex; NETs, Neutrophil extracellular traps; PASI, Psoriasis Area and Severity Index; DLQI, Dermatology Life Quality Index; PUFAs, Omega-3 polyunsaturated fatty acids; DHA, docosahexaenoic acid; EPA, eicosapentaenoic acid; MDA, malondialdehyde; MMP-1, metalloproteinase-1; COX-2, cyclooxygenase-2; JAK-2, Janus kinase 2; AP-1, protein activator-1.

AB and AO designed the review plan. SG and DZ provided help and advice as experts in this phield. IE ana-lyzed the data. VS interpreted data for the clinical and pre-clinical studies cited in the manuscript. AB, IE, VS and AO wrote the manuscript. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript.

Not applicable.

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This work was supported by the Russian Science Foundation (Grant # 23-45-00031).

The authors declare no conflict of interest.