Psoriasis and Exposome: Unveiling the Inner and the External Contributors of Psoriasis Disease

Abstract

The term “exposome” encompasses all the environmental elements, both infectious and non-infectious, that an individual encounters throughout life. It refers to the collective exposure to various factors in the environment that can have an impact on human health and finally result in a disease or affect the disease course. The exposome is a term implicated in all skin diseases including psoriasis. Ranging from lifestyle habits such as diet, smoking, obesity, sunlight exposure, pre-existing diseases, and infectious agents’ exposure to patients’ unique features such as skin microbes, oxidative stress parameters, skin chemical environment, and cutaneous immune reactions, skin seems to encounter a variety of different exposures. All these exposures in turn affect and contribute in distinct ways to the pathogenesis pathways implicated in the creation of the psoriatic skin lesions and shape the disease course and progression. Also, the interaction between environmental and genetic factors is a well-established disease contributor. This chapter discusses the link between each aspect of exposome and psoriasis pathways and mechanisms as well as treatment plans taking into consideration environmental factors. Understanding the exposome–psoriasis relationship would lead to implications and targeted interventions to mitigate possible risk factors and give future directions.

1. Introduction

Psoriasis is a persistent skin disease caused by immune system dysfunction and manifests with various phenotypically distinct subtypes such as plaque, guttate, pustular, or erythrodermic psoriasis. The disease, in its plaque form, which is the most frequent subtype, is characterized by well-defined, reddish, scaly plaques resulting from increased keratinocyte proliferation and proinflammatory cytokines. All forms are linked with genetic contributors, whose products are mainly involved in skin immune reactions and skin barrier formation [1].

The exposome represents all environmental exposures, from infectious and noninfectious causes that can contribute to the disease onset, making the hypothesis that everyone’s disease including psoriasis is the result of the individual history of exposures, considering the individual’s genetic susceptibilities. Apart from environmental exposures (air pollution, sunlight exposure) and lifestyle aspects (diet, exercise), exposome concept encompasses psycho-social practices while its yields such as epigenomics, transcriptomics, proteomics, and metabolomics as disease mechanisms are in the spotlight [2].

The pathogenesis of psoriasis is multifactorial, combining environmental and genetic factors and necessitating a further exploration of the concept of exposome. When individuals with a genetic predisposition encounter triggers for psoriasis, the adaptive immune system sets off a cascade of immune responses. The immunological pathways, specifically the IL-17 signaling pathway and its products, play a crucial role in driving the inflammatory cycle of psoriasis. More precisely, the myeloid dendritic cells release IL-12 and IL-23, with the IL-23 pathway being the primary driver in psoriasis pathogenesis as this cytokine supports the survival, differentiation, and activation of Th17 cells, which produce IL-17 cytokines. These cytokines, in turn, induce keratinocyte proliferation and promote the production of various psoriasis-related cytokines, chemokines, inflammatory mediators, and antimicrobial peptides. Pinpointing the psoriasis triggers and understanding their impact on specific aspects of psoriasis pathophysiology can pave the way for preventive strategies and practical application of the exposome concept [1].

Additionally, the presence of a disrupted skin barrier with impaired permeability plays a crucial role in the development of psoriasis. In susceptible individuals, skin injury can trigger psoriatic lesions, a phenomenon called Koebner phenomenon [3]. This process is likely mediated by the injury prompting keratinocytes to produce type 1 interferons, TNF-α, IL-6, and IL-36. In psoriasis, skin barrier dysfunction is also linked to the disruption of epidermal tight, gap, and adherent junction proteins. The reduced expression of these proteins likely contributes to increased transepidermal water loss and decreased hydration observed in psoriatic lesions [3, 4]. Therefore, mechanical or external exposures can contribute to the disease because of the compromised skin barrier.

Psoriasis disease is evaluated by the extent of skin involvement (body surface area (BSA)) and the severity of erythema, induration, and scaling, resulting in disease assessment scores such as the Psoriasis Area Severity Index (PASI). Treatment options include topical therapies such as vitamin D analogs (calcipotriol) or corticosteroids as well as phototherapy, systemic agents (methotrexate, ciclosporin and acitretin) and biologics such as TNF (adalimumab, etanercept, infliximab and certolizumab), IL-12/23p40 (ustekinumab), IL-23p19 (rizankizumab, guselkumab and tildrakizumab), IL-17 (ixekizumab and secukinumab), and IL-17 receptor (brodalumab) inhibitors. The combination of the proper treatment choice and the limitations of the exposome’s psoriasis modulatory factors can open new perspectives in the approach of psoriasis patients [1].

2. Inner contributors of psoriasis disease

The internal exposome pertains to individual-specific exposures within the body, encompassing genetic determinants, metabolic processes, and circulating blood biomarkers such as systematic oxidative stress parameters, hormones, and variability of skin as well as oral or gut microbiota [2].

2.1 Genetics and/or genomics of psoriasis

Basic principles: The evaluation of exposome factors affecting the onset of chronic diseases has focused on the analysis and the synergic effect with individual genetic variations induced by single-nucleotide polymorphism (SNP) and their associated proteome reactions. These genetic differences determine the patient’s susceptibility to developing a disease when exposed to specific exposome factors [5]. Genomics is a term relating all genes and their interrelationships in order to identify their combined influence on the growth and development of psoriasis.

Exposome aspect—Disease pathophysiology link: Psoriasis risk has been associated with regions of the genome with critical genes involved in systemic and skin immunity as well as skin barrier formation [5]. Notably, those SNPs that represent genes variants of the above-mentioned genes have shown significant associations in psoriasis patients compared with controls. Worth mentioning are SNPs of genes whose products are involved in immune pathways, such as IL-17/IL-23 axis, type I interferon signaling, antigen-presenting process as well as nuclear factor-κB (NF-κB) pathways. In addition to susceptibility, those gene variants have been implicated in the time of onset, severity, comorbidities, and response to the treatment. However, those factors alone are not sufficient to predict the psoriasis disease course [6].

Clinical correlations: This section also has promising clinical correlations focused on personalized medicine as well as psoriasis-targeted therapies.

2.2 Oxidative stress parameters and psoriasis

Basic principles: Oxidative stress conditions are determined by the imbalance between the production and accumulation of oxygen reactive species (ROS) in cells and tissues and the body’s ability by enzymatic and non-enzymatic mechanisms to detoxify these reactive substances. Under excessive oxidative stress, various cellular components, including membranes, lipids, proteins, lipoproteins, and deoxyribonucleic acid (DNA), are modified and lead to the formation of toxic and mutagenic products [7].

Exposome aspect—Disease pathophysiology link: UV radiation, air pollution, toxic substances, and their metabolites are responsible for the production of reactive oxygen and nitrogen species (ROS/RNS) [8]. ROS can also be produced due to polymorphisms of specific genes whose products regulate the redox balance and are often detected in psoriasis patients. ROS generated within the skin serves as chemo-attractants for neutrophils, which, in turn, can lead to further activation of neutrophils, creating a vicious circle [9]. Furthermore, oxidative stress promotes inflammation through several signaling pathways, mainly by NF-κB, that produce various cytokines and recruit additional inflammatory cells, leading to an augmented inflammatory response that preserves the chronic inflammatory nature of psoriasis [10].

Clinical correlations: Clinical correlations of oxidative stress are based on the assessment and comparison of oxidative stress parameters (toxic products, antioxidant enzyme activity, substrates of enzymatic reactions, etc.) in blood or tissue before and after an intervention or treatment initiation [11]. Skin and systematic oxidative stress have been implicated in many skin diseases including non-melanoma skin cancer [11]. In the study by Kökçam [12], the levels of glutathione (GSH), which is the most abundant antioxidant element in the cell and the activity of GSH-Px (GSH peroxidase) in both plasma and RBC samples were found lower in patients with psoriasis than in controls, whereas beta-carotene levels in plasma and MDA levels (lipid-oxidation parameter) in RBC samples were significantly higher in psoriasis patients, indicating higher systematic oxidative stress. Treatments for psoriasis, such as phototherapy and biologic systemic treatment, contribute to the induction of controlled oxidative stress, breaking the vicious circle between inflammation and oxidative stress [13]. An antioxidant diet including micronutrients such as polyphenols and carotenoids appears to have antioxidant characteristics with the following beneficial effect on skin [14], and topical application of antioxidants such as curcumin was proposed as an additional method to improve psoriasis disease’s lesions [15].

2.3 Pre-existing conditions as a trigger factor of psoriasis

Basic principles: The exposome includes pre-existing conditions that might increase the likelihood of developing psoriasis. Psoriasis is linked with various coexisting medical conditions, including cardiovascular and mental health disorders as well as other diseases associated with systemic inflammation such as psoriatic arthritis, Crohn’s disease, and ulcerative colitis [16].

Exposome aspect—Disease pathophysiology link: Increased levels of systemic inflammatory markers like C-reactive protein (CRP) may stem from interactions between proinflammatory cytokines IL-6, IL-1, and TNF-alpha. This elevation in inflammatory markers can potentially make patients more susceptible to experiencing negative cardiovascular events as well as developing psoriatic plaques. Regarding the link between skin and gut inflammation, Th17 cells in psoriatic skin produce IL-23, which is an essential cytokine for intestinal inflammation, leading to inflammatory bowel disease. In both instances, psoriasis can either be the initial diagnosed disease or occur subsequently. Depression and obesity will be discussed in the respective sections [16, 17].

Also, some medications used to treat specific diseases can lead to drug-induced psoriasis. For example, beta-blockers are widely prescribed for treating and preventing various medical conditions and block the beta-adrenergic subtype 2 receptors. As a result, adenyl cyclase is no longer activated, decreasing cAMP and intracellular calcium levels. This decrease disrupts the normal regulation of cell differentiation and promotes keratinocyte proliferation, which can have adverse effects on the skin [18].

Clinical correlations: It is crucial to conduct screenings for cardiovascular risk factors in psoriasis patients and, if heart disease is suspected, referred to the relevant specialists. Additionally, counseling patients on adopting healthy lifestyle habits such as proper diet, exercise, and smoking cessation is essential to minimize risk factors for comorbidities. Furthermore, the presence of concurrent diseases prompts specialists to adopt therapeutic approaches that do not negatively affect but benefit other systems [17].

2.4 Psoriasis and hormonal impact

Basic principles: Several studies examining the occurrence and severity of psoriasis in both genders indicated that psoriasis is more prevalent and severe in men compared to women, especially during periods of higher estrogen levels [19].

Exposome aspect—Disease pathophysiology link: Regarding sex hormones, estrogens inhibit the production of psoriasis-related cytokines like IL-1β and IL-23 by neutrophils and dendritic cells, respectively. However, in a psoriasis-control study, serum testosterone levels were significantly lower among psoriasis patients compared to control patients. It was also reported that testosterone promotes an immunological shift toward the Th2 phenotype [19]. Psoriasis severity in female patients can vary according to hormonal fluctuations, as psoriasis lesions tend to appear more frequently or worsen during puberty and improve during menopause. Pregnant women often experience complete resolution of psoriasis, but the condition may return after giving birth [20].

Thyroid hormones, specifically T3 (Triiodothyronine) and T4 (Thyroxine), trigger an elevation in epidermal growth factor (EGF) levels, resulting in epidermal hyperplasia or T3 itself promotes the proliferation of keratinocytes by T3 receptors on the skin. Stress, fast-modulation hormones, and circadian rhythm hormones will be discussed in the respective sections [21].

Clinical correlations: The immune-regulating effects of estrogen in psoriasis have been explored mainly in vitro studies. Additionally, findings from mouse psoriasis models indicated that targeted activation of estrogen receptor-signaling could be a promising new therapeutic approach for managing psoriasis, taking into consideration the adverse effects of estrogen therapy such as increased risk of thrombosis and endometrial cancer [19].

2.5 Metabolism profile (metabolics) in psoriasis patients

Basic principles: Metabolites directly reflect the biochemical processes occurring in a specific phenotype. They are the result-products of genomics and their associated proteomics and are closely linked to diseases and systemic conditions.

Exposome aspect—Disease pathophysiology link: In patients with psoriasis, insulin resistance and abnormal function of glucose transporter (GLUT) proteins have been observed, associated with susceptibility loci in metabolic diseases, including type 2 diabetes. Also, higher levels of α-ketoglutaric acid, lactic acid, aspartic acid, and glutamic acid are reported in psoriasis patients as these acids move in peripheral circulation and are consumed due to increased energy requirements related to cytokine production and rapid protein production due to cellular hyperproliferation. An excess of circulating free fatty acids can disrupt the β-pancreatic cell’s normal function, leading to insulin resistance. Adipocytes also secrete multiple inflammation-associated cytokines, triggering various inflammatory responses. In psoriatic lesions, the levels of unsaturated fatty acids, some of which have anti-inflammatory effects and anti-proliferative properties, differ significantly. Dysregulation in urea circle and in phenylalanine-tyrosine pathway can produce more ornithine and phenylalanine levels in the psoriatic lesions. The rapid proliferation and differentiation of the epidermis in psoriasis patients lead to changes in nucleotide metabolism in the peripheral circulation. These alterations primarily manifest as reduced levels of certain metabolites due to the increased demand and hypercatabolism of purines and pyrimidines.

Clinical correlations: According to certain studies, elevated levels of amino acids involved in the both urea cycle and collagen synthesis (proline and hydroxyproline) in the bloodstream and in psoriatic lesions are believed to be linked to the severity of psoriasis and, therefore, new psoriasis markers can be introduced. Each patient has a different genetic and metabolic profile, and therefore, treatment strategies with metabolomics integration can lead to individualized therapies.

2.6 Microbiome (skin, oral, and gut) role in the development of psoriasis

Basic principles: Microbiome refers to the symbiotic microbial cells harbored by each person, encompassing primarily bacteria in the gut, skin, and oral cavity. The microbiome plays a vital role in regulating the immune system of the respective organ or tissue. Its imbalance, called dysbiosis, occurring in the skin and/or gut microbiome, is linked to altered immune responses, resulting in disease occurrence. The composition of the skin microbiome is determined by the individual’s genetic factors as well as other exposome factors such as polymorphisms in filaggrin expression, hormonal factors, and variations in skin barrier function, indicating that one exposome factor can be influenced by the others, reinforcing the impact toward or against the onset of disease [22].

The skin and gut are heavily colonized by microbial cells, which in turn train the immune cells and determine the immunology capacity of the host. The gut–skin axis through the microbiome is a concept that has been referred to as skin disorders such as atopic dermatitis. The gut microbiome of infants with atopic dermatitis (AD) is characterized by lower levels of Bacteroidetes and Bifidobacterium and higher quantities of Clostridium and Escherichia, which, in turn, boost the inflammatory state in the intestine [23]. Those alterations in the gut microbiome disrupt the immune system balance by the production of inflammatory metabolites, which are released in the circulation and can affect skin. The Western diet and use of probiotics exacerbate and improve the skin manifestations of atopic dermatitis, respectively, indicating the existence of a skin-gut interaction, possibly by the microbiome [24].

Exposome aspect—Disease pathophysiology link: In case of psoriasis, the skin microbiome is mainly characterized by a relatively higher abundance of Staphylococcus aureus and Streptococcus species colonization and low quantities of immunoregulatory bacteria such as Staphylococcus epidermidis and Propionibacterium acnes [25]. This microbiome imbalance, mainly by Staphylococcus aureus, can trigger the production of IL-17 cytokine as defense mechanism of the skin. However, this IL-17 response fuels simultaneously pathogenic pathways of psoriasis. This microbiome imbalance exists both in psoriasis and not psoriasis lesions of the patient. Part of this microbial imbalance belongs to the decreased Actinobacteria-to-Firmicutes ratio, which is most prominent in skin lesions. Worth mentioning is that anti-psoriasis approaches such as UVB-light therapy and biology treatment change the microbiome diversity of the skin [26].

The skin-gut axis in psoriasis is not studied as deeply as in the case of atopic dermatitis. However, some structural variations have been reported, such as a decreased surface in the jejunum. This variation is responsible for differences in gut microbiome such as lower levels of Bacteroidetes and higher Firmicutes. Also, gut microbiome changes have been reported after biologic treatment such as secukinumab. Since the oral cavity is part of the gastrointestinal tract, a similar association is expected. An increased presence of oral Candida in patients with psoriasis has also been reported [23].

Clinical correlations-perspectives: A balanced skin microbiome helps to protect the skin from harmful pathogens and maintain its barrier function and therefore can be part of the psoriasis patient approach. The gut microbial composition and function are mainly influenced by dietary choices. Restoring the gut microbiome by diet, fecal transplants, and probiotics, can be used in patients with psoriasis and represent a promising preventive and therapeutic approach [23].

3. External contributors of psoriasis disease

The external contributors of exposome that promote psoriasis can be divided into general external factors (climate, biodiversity, urban environment, social, and economic elements) and specific external factors (infections, allergens, diet, tobacco, pollutants, and toxic substances) [27].

3.1 Environmental toxification and psoriasis disease

Basic principles: According to the 2019 Global Burden of Disease report, air pollution is the primary environmental risk factor for both adults and children. Carbon monoxide (CO), ozone (O₃), sulfur dioxide (SO₂), and nitrogen dioxide (NO₂) are among other monitored air pollutants due to their negative impact on health. When inhaled, these pollutants can enter the bloodstream, leading to oxidative damage and inflammation. Additionally, air pollutants can directly affect the skin upon contact [28].

Exposome aspect—Disease pathophysiology link: Bellinato et al. found that higher concentrations of different air pollutants were associated with psoriasis flares in patients living in an industrialized city [29]. Gaseous pollutants produce ROS and RNS species that overwhelm body’s antioxidant defenses, causing higher cutaneous and systemic oxidative stress conditions leading to psoriasis. Among gas pollutants, NO₂ increased the risk of psoriasis occurrence. After inhalation, air pollutants can cause oxidative stress in the airway’s epithelia but also reach peripheral tissues, such as skin, and due to oxidative stress—inflammation vicious circle, cause the production of proinflammatory cytokines that in turn are transferred into the bloodstream [30]. Also, direct skin contact with air pollutants can also add to the pathophysiology of psoriasis. Diesel exhaust particle exposure can trigger the activation of T cells present in the skin, leading to an abnormal release of proinflammatory cytokines such as TNF-α and interleukins (ILs) like IL-1 and IL-6 [29].

Clinical correlations—perspectives: It is crucial to understand that while pollutants can act as potential triggers and worsen psoriasis in some cases. Their impact, which seems to be unavoidable due to the industrialized way of everyday life, may vary among different individuals with psoriasis. Taking steps to minimize exposure to pollutants and adopting a healthy lifestyle can have positive effects on managing psoriasis and overall health.

3.2 Stress and psoriasis disease

Basic principles: Stress is widely recognized as a prominent trigger for psoriasis, and it has been linked with new onset as well as flare-ups of the disease. Psoriasis patients may experience anxiety because of the disease-related psychological burden of disfigurement, social stigmatization, or chronic itching. Furthermore, those stress feelings, along with dissatisfaction with treatment, may contribute to the development of depression in these individuals. Conversely, psoriasis can also be influenced or exacerbated by psychiatric conditions like depression and anxiety, creating a cyclical relationship [31].

Exposome aspect—Disease pathophysiology link: The pathogenesis link is based on the stress impact on immune function. Stress triggers the release of corticotropin-releasing hormone (CRH) in the hypothalamus, leading to elevated levels of adrenocorticotropic hormone (ACTH) in the bloodstream, which, in turn, induces the secretion of glucocorticoids (hypothalamic–pituitary–adrenal axis). CRH is also involved in the release of noradrenaline in the peripheral sympathetic nervous system and noradrenaline and adrenaline in the adrenal medulla, contributing to increased levels of neurohormones in the periphery. Immune system cells, such as T lymphocytes, B lymphocytes, and monocytes, express receptors for these hormones and therefore those cells’ activation in peripheral organs such as the skin can lead to cutaneous inflammation and cause psoriasis flare [32, 33].

Elevated levels of cytokines have been observed in stress-related disorders, as indicated by a study involving medical students that connected psychological stress was associated with increased levels of cytokines [34]. Cytokines’ levels were also assessed in psoriatic patients exposed to psychological stress. The salivary levels of IL-1β after stress stimuli were compared between psoriasis patients and control. Interestingly, after the stressful event, the control group showed an increase in IL-1β levels, while the psoriasis group did not, indicating an impaired immune system response to adrenergic stimuli [35]. However, this observation is not in line with the cytokine-mediated psoriasis flare-up that may be induced by stress.

In addition to acute experience of stress, chronic stress as well as depression has been linked to persistently high levels of proinflammatory cytokines, notably IL-6, TNF-α, and IL-1β. IL-6 and TNF-α can alter the metabolism of neurotransmitters like norepinephrine, serotonin, and dopamine, leading to depressive symptoms. Additionally, IL-6 promotes the production of Th17 cells and along with action of TNF-α, plays a central role in the development of psoriasis lesions [31, 32]. Additionally, the reduced levels of serotonin (5-HT) lead to increased production of certain inflammatory mediators like TNF-α and IL-1β [36].

Clinical correlations—perspectives: In clinical practice, those findings can be exploited by the development of drugs influencing the serotonergic and adrenergic systems to maintain the circulating levels of respective hormones to avoid a psoriasis flare-up. Research has already proved that anti-depressants have a protective effect on the risk of psoriasis in patients with Major Depressive Disorder. Individuals using antidepressants had a significantly lower risk of psoriasis compared to those who did not. Finally, further analysis revealed that the use of SSRIs (Selective Serotonin Reuptake Inhibitors) and lower dosages of antidepressants were associated with a statistically significant decrease in the risk of psoriasis [37].

3.3 Sleep habits and psoriasis-circadian rhythm

Basic principles: The circadian system comprises the master clock in the suprachiasmatic nucleus of the brain, serving as the central pacemaker and which regulates the daily rhythm of the other organs. An example of circadian rhythm is that of cardiovascular system, as there is a reduction in vascular tone and blood coagulability at night [38].

As for the skin, the pineal gland produces melatonin, which is a crucial regulator of the circadian balance. Melatonin levels follow the circadian rhythm, peaking at night and decreasing during the day. When exposed to light, melatonin levels promptly decline due to feedback inhibition, reducing its production. Melatonin is associated with hair growth, protection against ultraviolet (UV) damage in skin cells, wound healing, and antitumor effects [39].

Exposome aspect—Disease pathophysiology link: Psoriasis exhibits classical rhythmicity, with disease flares and associated symptoms such as itch and pruritus being more severe in the evening and worsening at night. The circadian clock plays a vital role in regulating various aspects of the immune system, and any disruption to this rhythm, whether through genetic alterations of central and peripheral regulators-components or changes in light-dark phases, significantly impacts immune response. Sleep deprivation resulted in increased levels of proinflammatory cytokines, including IL-1β, IL-6, and IL-12, leading to an intensified inflammatory immune response. This suggests that circadian disruption might contribute to the development and progression of psoriasis [38, 40].

Also, sleep loss is associated with function of the hypothalamic–pituitary–adrenal (HPA) axis, leading to psoriasis flare-ups as indicated in the stress-exposome, with increased secretion of cortisol and proinflammatory cytokines [38].

Clinical correlations—perspectives: The understanding of this exposome—parameter would lead to the identification of further intervention and enable targeted and personalized timing of psoriasis therapy to maximize treatment efficacy [40].

3.4 Diet and psoriasis

Basic principles: Diet plays a significant role in forming the composition of the gut microbiota, and therefore, the gut–skin axis discussed previously can affect the course of many skin disorders [41].

Exposome aspect—Disease pathophysiology link: Epidemiological studies have indicated that individuals with psoriasis had imbalanced dietary patterns, characterized by increased consumption of total fat and simple carbohydrates, which have been associated with activation of tumor necrosis factor-α/interleukin-23/interleukin-17 pathways, reactive oxygen species, and leukotrienes production and gut dysbiosis. Additionally, the diet that psoriasis patients usually adopt is characterized by reduced intake of proteins, complex carbohydrates, monounsaturated fatty acids, n-3 polyunsaturated fatty acids, vegetables, and fibers. This category of nutrients leads to the suppression of inflammatory pathways or induction of regulatory T cells, reducing the potential of inflammatory stimuli that can trigger psoriasis plaque formations [41, 42]. Worth mentioning is the lower intake of Mediterranean elements of nutrition (extra virgin olive oil, fruits, fish, and nuts) reported in psoriasis patients compared to healthy individuals. On the contrary, the Western diet has been accused of being a factor contributing to psoriasis. Indeed, after a short-term (4 weeks) exposure to a Western diet, there was an increase in the accumulation of IL-17 cells with enhanced expression of IL-23 receptors in imiquimod-induced psoriasiform dermatitis in murine models [41, 43].

Finally, the connection between obesity and psoriasis is well-established. As obesity progresses, adipocytes undergo senescence and dysfunction, altering their proteomic programming toward a proinflammatory phenotype. This shift may significantly influence the immune system’s function and serve as a critical factor in the development of various organ pathologies including the skin, as far as the skin is concerned, and cause chronic inflammation. Gut dysbiosis and microbiome dysregulation as well as lipid signaling are involved in the inflammatory process [42, 44]. Notably, individuals with a body mass index (BMI) of 35 or higher demonstrated an increase in the risk of developing psoriasis in women population [45].

Clinical correlations—perspectives: The manipulation of gut microbiota, for example, by targeted introduction of specific live organisms with probiotics, offers promising new possibilities in managing various immune-related conditions characterized by uncontrolled inflammation. Antioxidant and anti-inflammatory nutrients such as phenolic compounds have also been extensively studied and have shown significant potential in treating skin diseases like psoriasis. Additionally, emerging therapies such as bariatric surgery, in case of obesity, have a substantial impact on the therapeutic approach to an obesity-psoriasis patient. These advancements hold great promise for the future management of combined immune-related skin disorders such as psoriasis and obesity [46].

3.5 Exercise and psoriasis

Basic principles: Regular physical exercise, such as activities like walking, dancing, yoga, skiing, and gardening, plays a vital role in regulating the levels of ROS and RNS in cells, species that control the balance between the normal cellular adaptation to keep their homeostasis and, in case of excessive production and accumulation leading to high oxidative stress conditions and disease. Also, regular exercise enhances the functioning of the immune system by reducing adiposity and its associated inflammatory inducement. Moreover, exercise has been found to have beneficial effects on mental health, reducing psychological stress, anxiety, and depression [47, 48].

Exposome aspect—Disease pathophysiology link: Regular exercise reduces fat mass, which can subsequently reduce its contribution to systemic inflammation and, due to the brain–skin axis, can reduce stress and its impact on skin. The proposal of the authors regarding the amount of exercise to reduce the risk of psoriasis flare differs [48]. Goto et al. proposed that less than 1 hour of exercise per week was associated with incident psoriasis [49], while Frankel et al. concluded that the most active quintile had a lower risk of developing psoriasis compared to the least active quintile. Vigorous activity is also associated with a reduced risk of psoriasis [50].

Clinical correlations—perspectives: Engaging in exercise could serve as a beneficial preventive measure for psoriasis and may have the potential to improve the condition in overweight patients [48].

3.6 Sun exposure and psoriasis

Basic principles: Sunlight is composed of a spectrum of radiations that span from infrared to visible and UV light. The most well-known advantage of sun exposure is the synthesis of vitamin D, which is important for several physiological functions, especially maintenance of an adequate bone mineral density [51].

Exposome aspect—Disease pathophysiology link: UV radiation can modify the cytokine profile linked to psoriasis by steering the immune response away from the proinflammatory Th1/Th17 axis. The seasonal variation’s impact on the course of psoriasis is well known, with many cases experiencing relief during summer and exacerbation during winter. Some individuals reported worsening of their psoriasis due to photosensitivity. Also, UV radiation, especially UVB, leads to vitamin D production in the skin. Vitamin D can enhance the synthesis of anti-inflammatory cytokines by suppressing or inhibiting the production of proinflammatory cytokines like IL-6 and TNF-α, which are involved in the pathogenesis of psoriatic skin. As a result, vitamin D may have a considerable impact on the chronic autoimmune or inflammatory aspects of the disease [51]. Finally, there is a study that reports that vitamin D sufficiency acts as a protective factor against psoriasis flare-ups when a triggering factor occurs such as COVID-19 vaccination [52].

Clinical correlations—perspectives: Psoriasis patients can benefit from sun exposure as it can have positive effects on their skin condition. However, this also raises concerns about the increased risk of skin cancer in these individuals. Vitamin D supplements have been suggested as a potential method to improve psoriasis, but their effectiveness has not been conclusively demonstrated.

3.7 Alcohol and tobacco abuse

Basic principles: Nicotine is the primary alkaloid found in tobacco, and it is responsible for the addictive properties of tobacco products. Nicotine is rapidly absorbed not only through the alveolar spaces in the lungs but also through the skin and intestinal mucosa. The liver primarily metabolizes nicotine into several active metabolites. Nicotine interacts with different subtypes of nicotinic acetylcholine receptors, which are not only present in the nervous system and adrenal medulla but also in various other tissues, including skin keratinocytes and inflammatory cells like monocytes and dendritic cells, promoting inflammatory process. Apart from nicotine, tobacco consists of over 7000 chemicals, and smoking is known to be a risk factor for various human diseases [53].

Another abuse form that needs to be highlighted is alcohol consumption. Ethanol can affect cutaneous skin barrier as well as cutaneous immune reactions. Also, alcohol consumption is related to many other disorders such as obesity, depression, and liver disorders that can further exacerbate any skin disorder [54].

Exposome aspect—Disease pathophysiology link: Smoking induces oxidative stress and the generation of harmful free radicals, which disrupt signal pathways relevant to psoriasis, such as the NF-κB and JAK–STAT pathways. Moreover, nicotine stimulates the increased secretion of various cytokines such as (IL)-12, TNF, and IL-2, which play crucial roles in psoriasis pathogenesis. Furthermore, it has been observed that smoking can also influence the expression of vascular endothelial growth factor, an essential factor in angiogenesis. Although the risk of psoriasis in subjects with a smoking duration of <10 years was almost the same as that of nonsmokers, a smoking duration ≥30 years led to twice the risk of psoriasis compared to nonsmokers individuals [55, 56].

Ethanol can be detected within human skin, being secreted by eccrine glands, mainly sweat glands, or through passive diffusion, and by its metabolites can enhance the proliferation and mRNA expression of proliferation-associated genes of keratinocytes, disrupting the skin’s barrier function and increasing its permeability. Moreover, alcohol also affects lipid metabolism, affecting the lipid composition of the skin barrier. Also, the metabolism of ethanol is associated with the production of ROS. As a result, both ethanol and the produced ROS formed during ethanol metabolism generate an inflammatory environment and trigger psoriasis by regulating different signal transduction pathways and inducing the production of various proinflammatory cytokines in lymphocytes, macrophages, and keratinocytes [54].

Clinical correlations—perspectives: Quitting smoking could be a significant goal in preventing and managing psoriasis by ceasing smoking. The level of smoke-induced inflammation might decrease, either through a reduction in circulating inflammatory cytokines or the restoration of T-cell impairments. Patients with psoriasis should receive counseling regarding the restricted use of alcohol, as it is associated with a higher risk of worsening the disease and its related comorbidities. Additionally, considering the potential impact of alcohol on concurrent pharmaceutical medications is important (avoidance of the combination of methotrexate and alcohol consumption due to risk for liver damage) [54, 57].

3.8 Mechanical trigger of psoriasis lesions

Basic principles: Several research studies emphasize the influence of mechanical forces and mechano-transduction in the initiation of the disease, leading to the activation of inflammation signaling pathways in keratinocytes [58].

Exposome aspect—Disease pathophysiology link: A typical example, widely known as Koebner phenomenon, involves the development of psoriatic plaques in apparently healthy skin following trauma and/or mechanical stress (scratches, abrasion, pressure from tight shoes, shaving, etc.). In case of psoriasis, the normal mechano-induced signaling pathways and molecules that translate mechanical forces to biochemical signals seem to be impaired (dysfunctional ion channels, protein pathways, and resulting abnormal destruction of tight junctions) [58].

Tattooing involves permanently marking the body with exogenous pigments or dyes introduced into the dermis for artistic purposes. The Koebner phenomenon, where psoriatic lesions develop at the site of skin trauma, has been documented in several case reports and one case series of patients with psoriasis who had tattoos [59].

Clinical correlations—perspectives: The exploration of mechano-transduction and mechano-sensing mechanisms is not adequately studied and, in case of psoriasis, can offer potential opportunities for identifying novel therapeutic targets [58].

3.9 Psoriasis and infectomics

Basic principles: Infection serves as an external trigger for psoriasis, as indicated by the well-established connection between the guttate psoriasis and acute streptococcal infection. Various infectious agents as the bacterium Helicobacter pylori, the fungi species Malassezia and Candida, as well as viral infections like human immunodeficiency virus (HIV), human papillomavirus (HPV), and hepatitis C virus (HCV) infection, along with the mite species Sarcoptidae are considered to be possible infectious triggers of psoriasis. Those infections seem to affect the immune cells, producing inflammatory cytokines that can initiate or worsen psoriasis [60, 61].

Exposome aspect—Disease pathophysiology link: Superantigens represent a classical mechanism by which bacteria can contribute to the formation of a psoriatic plaque. The connection between the outer surface of MHC class II proteins on antigen-presenting cells and T-cell receptors on the surface of T helper cells leads to their proliferation and cytokine production, such as IFN-γ. Additionally, superantigens enhance T-cell expression, promoting Th17-dominated responses and contributing to the pathogenesis of psoriasis [62].

In case of streptococcal infections and other Gram-positive organisms, the streptococcal cell wall is predominantly composed of peptidoglycan (PG), which is regarded as a potentially proinflammatory element and, therefore, another psoriasis mechanism can be observed besides superantigen action [63]. Additionally, serum anti-Helicobacter pylori immunoglobulin G (IgG) has been reported to be high in psoriasis patients, and their levels are connected with severity or duration of the disease [64, 65]. In case of viral hepatitis and HIV infection, common pathophysiology links have been reported such as the overproduction of TNF-α in HCV and changes in the constitution of lymphocyte subpopulations [66]. Psoriasis exacerbations and new onsets as well as new subtype psoriasis occurrences (such as pustular form in a patient with plaque psoriasis [67]) have been documented in case of COVID-19 infections and post-COVID-19 vaccinations [68]. The etiology proposed was the hyperinflammation state in both cases. Fungal infections, such as Malassezia and Candida, can predispose to psoriasis by Th1/Th2 cytokine imbalance and superantigen reaction, respectively [61].

Clinical correlations: Treatment options like antibiotics or tonsillectomy have been suggested for guttate psoriasis and flare-ups of chronic plaque psoriasis. The association between antibiotics and psoriasis has been a topic of discussion for many years, with reports of improvement, onset, or worsening of psoriasis observed after antibiotic treatment [61].

4. Discussion

The exposome is a complex area of scientific research that profoundly influences health. This concept provides a comprehensive understanding of the various exposures individuals encounter during their lifetime including internal and external environmental factors that can influence the onset and progression of specific diseases. Some aspects of the exposome, particularly external contributors, can be modified, such as quitting smoking, leading to potential positive effects on the disease [2]. Also, some external contributors can ameliorate the disease, such as sunlight-induced cutaneous immunosuppression [51].

Clinical perspectives on the exposome and the integration of internal factors like genomics with external contributors like diet are crucial in personalized medicine, promising a better approach to treating patients with psoriasis. Moreover, external exposure factors can trigger disease onset directly, as seen in the case of unhealthy diets which cause systemic inflammation and trigger psoriasis mechanisms. Additionally, these external factors can modify internal exposome factors, as a high-fat diet can lead to gut dysbiosis, which can worsen psoriasis through the gut–skin axis. The interaction between internal and external exposome factors plays a significant role in the development of psoriatic disease, with combinations like exercise-induced oxidative stress and stress-induced hormonal impacts (Figure 1). The result of those combinations as well as the direct effect of external and internal contributors can lead to systemic and cutaneous inflammation, leading to psoriasis (Figure 1). Understanding this interplay is of utmost importance in comprehending the complexities of psoriasis.

Figure 1.

The interaction between genomics, other internal contributors of exposome (oxidative stress parameters, metabolics, microbioma, hormonal impact), external contributors (sunlight, exercise, diet and stress), and main pathogenesis of psoriasis disease (skin inflammation) by single or bidirectional pathways (created by biorender.com).

However, some questions arise on whether an exposome variant is adequate for the expression of a disease phenotype or whether genomics is the indispensable inner contributor. A study showed that polymorphisms of the glutamate cysteine ligase catalytic subunit that regulates glutathione biosynthesis (GCLC) combined with tobacco smoking and alcohol abuse are significantly associated with the risk of psoriasis and related to its clinical features [69].

Also, the impact of exposomes on psoriasis disease seems to depend on the psoriasis stage. During the initiation stage, new inflammatory lesions continually emerge, while during the stationary stage, the lesions stabilize. Also, early and chronic psoriasis diseases differ in terms of immunology. In the initiation stage, the IL-23/IL-17 axis and activated DCs are the main contributors to the disease, while in chronic disease, mature dermal DCs and T cells contribute to the cytokine milieu [1]. Therefore, the result of exposome factors depends on the psoriasis stage. Also, the treatment status of psoriasis patients can defend against the psoriasis-provoking actions of some exposome factors. For example, patients under biologic treatment showed less frequent episodes of psoriasis flare-up following COVID-19 vaccination [67].

5. Conclusion

Exposome represents a multifaceted area of research that significantly impacts our understanding of psoriasis. This concept provides a comprehensive view of how various internal and external environmental factors interact to influence the onset and progression of psoriatic disease. More research in exposome in psoriasis disease is needed as its further exploration may open exciting possibilities for personalized medicine and targeted therapies.

Conflict of interest

The authors declare no conflict of interest.