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ORIGINAL ARTICLE
Year : 2022 | Volume
: 42
| Issue : 2 | Page : 133-136
Tissue and serum lipoxin A4 levels in psoriasis patients and their relation with disease severity
Rehab Mohamed Naguib MD 1, Hanan Abo Zaid Mohamed Al Nemr2, Laila Ahmed Rashed3, Reham William Naguib4
1 Lecturer of Dermatology, Dermatology & Venerology Department, Faculty of Medicine, Beni-Suef University, Egypt
2 Dermatology & Venerology Department, Faculty of Medicine, Beni-Suef University, Egypt
3 Professor of Biochemistry, Cairo University, Egypt
4 Assistant Professor of Dermatology, Dermatology & Venerology Department, Faculty of Medicine, Beni-Suef University, Egypt
Correspondence Address:
Rehab Mohamed Naguib
19 Port Saed Street, Beni Suef, 62511
Egypt
Source of Support: None, Conflict of Interest: None
CheckDOI: 10.4103/ejdv.ejdv_33_21
Background Psoriasis disease is a chronic hyperproliferative inflammatory disease, in which genetic and environmental factors have an important role, but the exact cause is yet unknown. Lipoxin A4 plays a role in improvement of psoriasis cases, it blocks the production of the proinflammatory cytokine tumor necrosis factor with increasing the production of the anti-inflammatory cytokine, c–c chemochine receptor-5 by T lymphocytes, and it reduces the perception of pain due to inflammation.
Aim Detection of the expression of lipoxin A4 in the tissue and serum of psoriatic patients as compared with normal-control persons to investigate the possible role of lipoxin A4 in the psoriasis pathogenesis and its correlation with disease severity.
Patients and methods The present study included 25 psoriatic patients and 25 age, sex-matched healthy controls. Four-mm punch-skin biopsy was taken from patients (psoriatic lesion) and control persons and it was kept in lysis solution for the stability of the studied parameters and it was kept frozen at –80°C till analysis of lipoxin A4 by PCR. Peripheral blood samples for detection of serum lipoxin A4 were taken. Blood samples were centrifuged and the serum was stored at –80°C and used for enzyme-linked immunosorbent assay.
Results Psoriatic patients had significantly lower tissue and serum lipoxin A4 levels as compared with normal-control persons.
Conclusions Lipoxin A4 could contribute to psoriasis pathogenesis through its immunomodulatory role.
Keywords: enzyme-linked immunosorbent assay, lipoxin A4, psoriasis, real-time PCR
Psoriasis is a chronic autoimmune, genetic, inflammatory disease. It is associated with a lot of comorbidities and a high socioeconomic burden. Psoriasis patients also experience a decreased quality of life as a result of this disease [1].
The pathogenesis of psoriasis is under active investigation, with many studies that aim to identify the genetic susceptibility loci for the disease to determine novel targets for the systemic therapies. Basic and translational researches have led to understanding of both Th-1 and Th-17 pathways involved in development of psoriasis [2].
Lipoxins are derived from arachidonic acid, an omega (ω)-6 fatty acid. They can be defined as arachidonic acid metabolites that contain three hydroxyl residues and four double bonds. This structural definition distinguishes them from other specialized proresolving mediators (SPMs), such as the resolvin, neuroprotectin, and maresin, which are the metabolites of omega-3 fatty acid, eicosapentaenoic acid, or docosahexaenoic acid, also other metabolites that are derived from other polyunsaturated fatty acids. All of these other SPMs have many activities and functions similar to the lipoxins [3].
Lipoxins are anti-inflammatory, proresolving molecules that are secreted by the immune cells like neutrophil and macrophage cells. Lipoxins are metabolites of the arachidonic acid pathway. Arachidonic acid pathway plays important roles in the inflammation, producing several anti-inflammatory molecules [4].
Lipoxin A4 and its analog suppress inflammatory reaction by modulating high-mobility-group box-1 (HMGB1) expression and translocation in the psoriasis disease. HMGB1 acts as an inflammatory cytokine when secreted extracellular in psoriatic lesions and is involved in development of the psoriasis disease [5].
The value of this work is to assess the serum and tissue level of lipoxin A4 in patients of psoriasis to evaluate its possible role in pathogenesis of psoriasis disease and may be its use as therapeutic modalities.
Patients and methodsThis case–control study included 25 patients with chronic plaque psoriasis and 25 age-matched and sex-matched healthy controls. The patients and controls were recruited from individuals attending the outpatient clinic of Beni-Suef University Hospitals in the period from November 15, 2019 to April 22, 2020.
Exclusion criteria included the use of any topical or systemic treatment for psoriasis in the last 3 months, patients with other types of psoriasis, or with associated systemic or dermatological diseases.
Patient information was collected by one dermatologist, including age, sex, type of psoriasis, affected body-surface area according to the rule of nines [6], and disease activity determined by psoriasis area and severity-index score.
The aim of our study was explained to each patient and a written consent was taken before data collection, the protocol of the study conforms to ethical guidelines of the 1975 Declaration of Helsinki as reflected in the priori approval by Institution Human Research Committee.
ResultsThe sex ratio and age were not substantially different for each variable among patients with psoriasis (nine women, 16 men, mean±SD age 48.56±12.2 years), and healthy controls (four women, 21 men; mean±SD age 50.24±7.1 years). Clinical data of participants are presented in [Table 1].
Table 1 Dermographic data, clinical characteristics of the psoriasis patients, and controlsThe tissue and serum lipoxinA4 expression
The tissue lipoxin A4 level in the cases ranged from 1.01 to 7.8 ng/ml with a mean of 2.94±1.7 ng/ml. In addition, the lipoxin A4 levels in the controls ranged from 4.5 to 14.7 ng/ml with a mean of 9.45±2.26 ng/ml. The mean serum LXA4 level in the patients and control groups was 1.73±0.67 and 8.99±2.15 ng/mg, respectively ([Table 2]). The association analysis showed a statistically significant association between psoriasis disease and lipoxin A4 level (P<0.001). Psoriasis patients had significantly lower tissue and serum lipoxin A4 level ([Figure 1] and [Figure 2]).
The correlation analysis showed no significant correlation between lipoxin A4 expression and age (P=0.755), psoriasis area and severity-index (P=0.197), and duration of disease (P=0.606).
The detection of lipoxin A4 in the tissue was performed using the quantitative reverse-transcription PCR (qRT PCR): total mRNA was extracted from specimens with TRizol Reagent (Applied Biosystem, Otsu, Japan). After RNA extraction, reverse transcription from total RNA to cDNA was performed with a Prime Script RT Reagent Kit. PCR was performed with SYBR Green PCR master mix (Applied Biosystem).
Detection of serum lipoxin A4 level was performed using enzyme-linked immunosorbent assay. Blood samples had been collected from antecubital vein and centrifuged at 3500 rpm for 15 min. Serum samples were collected in Eppendorf tubes and stored at –80°C, until analysis of lipoxin A4 using enzyme-linked immunosorbent assay kits (Cusabio Biotech, Wuhan, China). The lipoxin A4 levels were expressed as ng/ml. All data had been analyzed with the ABI Prism sequence-detection system software and quantified using the v1.7 Sequence detection software from the PE Biosystems. The relative expression of the studied genes has been then calculated using comparative threshold-cycle method.
Statistical analysis
Excel spreadsheets were established for entry of data. We used the validation checks on numerical variables and option-based data-entry methods for categorical variables to reduce the potential errors. The analysis was carried with the SPSS software (Statistical Package for the Social Sciences, version 24; SSPS Inc., Chicago, Illinois, USA). Frequency tables with percentages were used for the categorical variables and descriptive statistics (median and interquartile range) were used for the numerical variables. Independent Student t tests, paired t tests, or Mann–Whitney tests had been used to compare quantitative variables, while the χ
2 tests or McNemar–Bowker tests had been used to analyze categorical variables. A P value less than 0.05 is considered statistically significant.
DiscussionPsoriasis is an inflammatory systemic disease that is characterized by release of many proinflammatory cytokines from the immune cells, as well as activation of the innate and adaptive immune systems that cause long-term damage to multiple tissues and organs. It has been associated as well with numerous comorbidities, including cardiovascular, rheumatological (psoriatic arthritis), and psychiatric complications, and has also negative effects on patient’s quality of life [7].
Psoriasis is a disorder of the immune system in which keratinocytes, dendritic cells, and T cells have central roles. It can be triggered by various factors in genetically susceptible individuals, including trauma, infection (such as streptococcal infection), and medications (such as β-blockers, IFN-α, and lithium). Many abnormalities have been observed involving antigen presentation, activation of nuclear factor kappa B signaling pathways, differentiation of T-helper cell populations (especially T-helper 17 cells, which are the primary source of interleukin-17), and enhanced interleukin-17 response, which promotes the host’s immune response and infiltration of immune cells [8].
A lipoxin (LX or Lx) has important potent dual proresolving and also anti-inflammatory properties, and it is a bioactive autacoid metabolite of arachidonic acid made by many cell types. They are categorized as nonclassic eicosanoids and members of the SPMs, family of polyunsaturated fatty acid metabolites. Like other SPMs, LXs are formed during inflammation, then act to resolve, inflammatory responses, two lipoxins have been identified, lipoxin A4 (LXA4) and lipoxin B4 (LXB4), but studies have identified epimers of these two LXs: the epilipoxins, 15-epi-LXA4 and 15-epi-LXB4, respectively [9].
LXA4 was found to cause suppression of leukocyte-mediated injury, also, it promotes the chemotaxis of monocytes and phagocytosis of apoptotic neutrophils, and inhibits production of many proinflammatory cytokines and also cell proliferation [9]. It is reported that human-blood neutrophils, when being stimulated, make these two lipoxins and that neutrophil cells, when stimulated by either of the LXs, mounted superoxide anion (O2
–) generation and degranulation responses. Both these responses are known to be proinflammatory, while aimed at neutralization of the invading pathogens and digestion of the foreign materials, could contribute to damage of the host tissue and so prolonging and promoting further inflammation. Subsequent studies found that these lipoxins, and their epimers, epi-LXA4 and LXB4, act to resolve and dampen the inflammation, that is, they are anti-inflammatory cell-signaling agents [10].
There is a scarcity in the published literatures regarding the role of LXA4 in the psoriasis pathogenesis and its protective effects. Therefore, we conducted the present prospective, case–control, study in order to evaluate the level of LXA4 in patients with psoriasis and its correlation with clinical parameters.
This study showed that the level of LXA4 is significantly downregulated in patients with psoriasis, compared with healthy volunteers.
Liu et al. [11] investigated the effects of LXA4 on the HMGB1-signaling cascade and inflammation in lipopolysaccharide-induced keratinocytes and imiquimod-induced psoriasiform dermatitis in mice. The authors found that treatment with LXA4 agonists caused attenuation of the development of imiquimod-induced psoriasiform dermatitis.
Treatment with lipoxin A4 inhibited the translocation of HMGB1 from the nucleus to cytoplasm and causes downregulation of the expression of toll-like receptor 4, nuclear factor kappa B-p65, phosphorylated extracellular signal-regulated kinase (p-ERK1/2), and many proinflammatory cytokines in vivo and in vitro [12]. These findings indicate that lipoxin A4 and its analog might be potential therapeutic candidates for psoriasis disease due to their ability to affect the translocation and also the expression of the HMGB1.
Similarly, Lewandowska-Polak et al. [13] assessed the influence of LXA4 on inhibition of synthesis of proinflammatory cytokines by peripheral blood mononuclear cells of patients with psoriatic arthritis. The study group consisted of 10 patients with psoriatic arthritis and five healthy controls. Incubation of cells with lipopolysaccharide increased production of all cytokines assessed either in patients with the psoriatic arthritis or in healthy controls. In PBMCs from patients, incubation of cells with LXA4 decreases production of the proinflammatory cytokines.
Study’s limitations
We acknowledge that the study has some limitations. The sample size of the included patients was relatively small and from a single center, which may limit the possibility that the study’s results can be generalized to the general population.
Conclusion of the studyThere is a significant dysregulation of lipid mediators in patients with psoriasis. The study showed that the level of LXA4 is significantly downregulated in patients with psoriasis, compared with healthy volunteers. Our findings highlight that LXA4 and its analog may be important therapeutic candidates for psoriasis. Nevertheless, further trials that assess the importance of LXA4-based therapeutic options are still needed.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
References
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