Recent studies have demonstrated significant changes in serum adipokine levels in psoriasis patients 1. Chemerin is a newly identified adipokine and antagonist of chemokine-like receptor 1 (CMKLR1), which is expressed by cells of the innate immune system 2. Chemerin is structurally and evolutionarily related to the cathelicidin precursors and is known to stimulate chemotaxis of plasmacytoid dendritic cells (pDCs) and neutrophils and to regulate adipogenesis. Overexpression of cathelicidin in psoriatic lesions suggests an involvement of chemerin in the development of psoriasis by modulating skin innate immunity 3. Moreover, chemerin cleavage generates a potent anti-inflammatory peptide that also signals through ChemR23 and suppresses inflammation 4.
High systemic chemerin levels were found to be an independent marker of metabolic syndrome (MetS) 1, which has been reported to be associated with an increased risk for psoriasis or its increased severity 5.
The present work aims to study serum and tissue levels of chemerin in psoriatic patients and control individuals and to investigate the possible relationship between serum and tissue chemerin levels and the presence of MetS among these patients.
Patients and methods
Twenty patients with active psoriasis vulgaris attending the Dermatology Outpatient Clinic of Kasr El Aini Hospital in Cairo University were randomly enrolled for this study. Patients had not used any medication apart from topical emollients for 2 weeks. Ten age-matched and sex-matched healthy individuals volunteered as controls. The study was approved by the Research Ethics Committee at the Dermatology Department, Cairo University Hospital (Cairo, Egypt). The patients and controls signed an informed consent to participate in this study.
Personal and clinical data including age, sex, body weight, height, BMI, waist circumference (WC), history of smoking, and history of cardiovascular disease (CVD) were reported in both patients and controls. The duration of disease, age at onset, family history, psoriasis area and severity index (PASI) score 6, and extent of disease were assessed by the rule of nine 7. In both groups, blood pressure readings, serum lipids, blood glucose levels, homeostasis model assessment for insulin resistance, and presence of MetS, which are predictors of CVD 5, were also assessed in both groups. Diagnosis of psoriasis was made on a clinical basis. The extent and severity of disease were assessed using PASI score. For definition of MetS, we adopted the worldwide definition of the new International Diabetes Federation MetS 8. According to this definition, for a person to be defined as having MetS, he must have central obesity plus any two of four additional factors:
- raised triglycerides level: at least 1.7 mmol/l (150 mg/dl);
- reduced high-density lipoprotein cholesterol: less than 1.03 mmol/l (40 mg/dl) in male patients and less than 1.29 mmol/l (50 mg/dl) in female patients (or had undergone specific treatment for these lipid abnormalities);
- raised blood pressure: systolic at least 130 or diastolic at least 85 mmHg (or had undergone treatment for previously diagnosed hypertension);
- raised fasting plasma glucose: at least 5.6 mmol/l (100 mg/dl) [or had been diagnosed with type 2 diabetes mellitus (DM) previously].
According to the new International Diabetes Federation definition, central obesity is measured by WC with cutoff points that are sex and ethnic-group specific. For example, an abnormal WC for European male patients is at least 94 cm and that for European female patients is at least 80 cm. We used the European measurements for our patients, as there are still no specific data for Middle East populations, and it is recommended to use European data until more specific data are available 8.
After an overnight fast, venous blood samples of 5 ml were collected and immediately processed in EDTA tubes. After 15 min of centrifugation at 1000g, the plasma was rapidly pipetted off and kept frozen at −80°C until analysis.
Two punch biopsy samples from each patient (lesional and nonlesional skin) and one skin biopsy sample from normal skin of controls were obtained and kept frozen in 1 ml protein extraction.
Serum chemerin was examined using an enzyme-linked immunosorbent assay. The kit is manufactured and distributed by Quantikine R&D System Inc. (Minneapolis, Minnesota, USA). Tissue chemerin was measured by homogenizing 30 mg of tissue specimen in 1 ml lysis buffer for protein extraction. This buffer contained 0.0625 mol/l Tris buffer (pH 6.8), 2% SDS, 3% 2-mercaptoethanol, 10% glycerol, 10 μg/ml aprotinin and 1 mmol/l phenyl methyl sulphonyl fluoride (Sigma, St Louis, Missouri, USA). After cell lysis the homogenate was centrifuged at 8000 rpm for 20 min at 4°C. The supernatant was kept frozen at −70°C until analysis 9.
Data were statistically described in terms of mean±SD, frequencies, and percentages when appropriate. Comparisons between groups were made using the χ2-test and Fisher’s exact test for qualitative variables. An independent sample t-test was carried out for normally distributed quantitative variables. The Mann–Whitney U-test was used for quantitative variables that are not normally distributed. Correlations were determined to test for linear relationship between variables. The significance level was set at a P value equal to 0.05. Linear regression analysis was performed to test for predictors of changes in the levels of plasma and tissue chemerin. Clinical parameters such as BMI, WC, and the presence of psoriasis, MetS, DM, and dyslipidemia were included in the model. A multivariate logistic regression analysis was performed for detection of the predictors of high serum and tissue chemerin. Statistical analyses were performed using a software package Statistical Package for the Social Sciences version 15.0 for Windows (SPSS Inc., Chicago, Illinois, USA).
Epidemiological data for patients with psoriasis and controls are presented in Table 1.
More number of patients with MetS, obesity, DM, and dyslipidemia were detected in the psoriasis group than in the control group, but these differences were not significant (P=0.064, 2.852, 0.260, 0.210, and 0.260, respectively). Insulin resistance (IR) was significantly higher in psoriasis patients than in controls, as it was observed in 40% of patients but was absent in all healthy individuals (P=0.029).
Higher values of mean BMI (28.5±5.76 vs. 26.90±3.73 kg/m2; P=0.426) and WC (91.25±14.82 vs. 83.90±12.87 cm; P=0.193) were detected in patients with psoriasis compared with controls, with no statistical significance. Smoking status was not significantly different between the groups, as it was detected in 45% of patients and 40% of controls (P=0.7). Between the studied groups, there was no significant difference in the prevalence of CVD (P=1) and hypertension (P=1).
The presence of MetS among patients was associated with higher PASI scores (P=0.029) and WC (P=0.026).
The PASI score was significantly higher in patients with DM than in nondiabetic individuals (P=0.029). Moreover, positive correlations were detected between PASI score and WC of patients (P=0.009). A positive correlation was detected between the extent of disease and BMI of patients (P=0.048).
Levels of chemerin in plasma
The mean plasma levels of chemerin in patients and controls were 52.45±11.83 and 9.4±1.6 μg/ml, respectively. The difference was statistically significant (P<0.001) (Fig. 1). A negative correlation between the level of serum chemerin and duration of psoriasis was detected in our patients (r=−0.517, P=0.02) (Fig. 2). To test the predictors of serum chemerin levels, age, sex, smoking habits, presence of psychic stress, hypertension, and the presence of psoriasis were tested. Only the presence of psoriasis was found to be a statistically significant predictor of serum chemerin levels [regression coefficient (RC) 45.2 μg/ml, 95% confidence interval (CI) 34.9–55.4, P<0.001].
Levels of chemerin in tissue
The mean tissue levels of chemerin in psoriatic lesions, normal skin of psoriatic patients, and in normal skin of controls were 28.1±9.28, 13.34±4.23, and 5.22±1.98 ng/mg protein, respectively. Significant differences were detected between lesional skin of patients and normal skin of controls (P<0.001) and between the nonlesional skin of patients and normal skin of controls (P<0.001) (Fig. 3). However, no significant difference was detected between lesional and nonlesional skin of patients (P=0.795). Tissue chemerin did not correlate with plasma chemerin levels (P=0.986). To test the predictors of chemerin levels in lesional tissue, age, sex, smoking habits, the presence of psychic stress, hypertension, and the presence of psoriasis in patients were also tested. The presence of psoriasis and psychic stress was found to be a statistically significant predictor of tissue chemerin levels (RC 16.9 μg/ml, 95% CI 11.33–22.59, P<0.001 and RC 9.1 μg/ml, 95% CI 3.77–14.38, P=0.002, respectively).
According to this work, plasma and tissue concentrations of chemerin were significantly elevated in psoriasis patients compared with controls, and these elevations were significantly associated with the occurrence of psoriasis. Moreover, serum chemerin levels in psoriatic patients were significantly negatively correlated with the duration of disease. High serum chemerin levels in psoriatic patients were also reported by Nakajima et al.1, but, in contrast to our findings, they reported higher levels of tissue chemerin in the epidermis of involuting psoriatic lesions compared with healthy controls. Moreover, Albanesi et al.3 also demonstrated higher epidermal expression of chemerin in healthy, uninvolved psoriatic skin than in plaque lesions. In contrast, they detected higher chemerin expression in fibroblasts of active psoriatic lesions compared with normal skin of psoriatic patients and healthy skin of controls, which is in agreement with our observations and could be because we measured protein expression of chemerin in both the dermis and epidermis of the skin and not only in the epidermis.
Chemerin is the only chemotactic factor known to induce the migration of pDCs in vitro10. We found that higher chemerin levels were associated with earlier onset of psoriasis, which might reflect a more evident role of chemerin in the initiation of psoriatic lesions and explains the infiltration of pDCs. These cells were considered as key effector cells that activate T cells through the release of interferon-α 11 in psoriatic skin during the early phases of psoriasis by Albanesi et al.3, whereas they were almost absent in long-lasting lesions.
It was also speculated before by Albanesi et al.3 that chemerin may have dual but opposite roles in the pathogenesis of psoriasis: first, a role in the recruitment of pDCs during the early phase, and another role in the attenuation of inflammation in involutional lesions. In support of this hypothesis, Cash et al.4 showed that a chemerin-derived peptide exerted an anti-inflammatory role in suppressing neutrophil and monocyte recruitment.
The presence of higher chemerin levels in normal skin of psoriatic patients compared with controls reflects the potential of these sites to recruit pDCs and initiate early psoriatic lesions, as pDC accumulation precedes the clinical expression of psoriasis 3.
In the current work, serum chemerin levels did not correlate with PASI score and this was in agreement with the results of Nakajima et al.1.
Although chemerin is known to be associated with a wide range of markers of MetS, and alterations in chemerin serum concentrations have been demonstrated to reflect adipose tissue dysfunction and an early pathogenic event in diabetes 12, we found no significant correlation between serum chemerin levels and the presence of MetS or any of the predictors of CVD in our patients. In contrast to the results of Nakajima et al.1, who demonstrated a positive correlation between serum chemerin levels and the presence of hypercholesterolemia and hypertriglyceridemia, the current work did not establish any relationship between serum chemerin levels and lipid abnormalities in the studied patients. Moreover, serum chemerin levels did not correlate with the BMI of patients, which, however, was in agreement with the results of Nakajima et al.1.
Although researchers found a significant relationship between the occurrence of psoriasis and cardiovascular risk factors 5,13,14, we did not find a significant relationship between the occurrence of psoriasis and hypertension, DM, dyslipidemia, and obesity, in addition to ischemic heart disease and smoking; this may be because of the limited number of patients in this study. However, IR, which is a risk factor for CVD, was significantly more prevalent in psoriasis patients compared with controls. This could be because of the effect of the chronic state of inflammation characteristic of psoriasis, as chronic inflammation has been suggested to be a part of the IR syndrome 15.
In our study, the prevalence of MetS among patients was associated with higher PASI scores. This is in agreement with the study by Grundy et al.16, as MetS is characterized by an increase in the activity of Th1 cells, similar to psoriasis, which suggests that psoriasis may be associated with MetS because of shared inflammatory pathways 17. We also observed that WC and BMI were positively correlated with the extent of psoriasis; hence, obese patients, according to our work, tend to have more extensive disease, affecting higher body surface area, compared with lean patients. This could be explained by the fact that visceral adiposity is associated with an elevation of tumor necrosis factor-α and interleukins-6, which play multiple roles in inflammation, metabolism, and endothelial cell function regulation 18,19.
We could therefore conclude that serum and tissue chemerin levels are elevated in psoriasis patients compared with healthy controls but are not related to the presence of MetS or any other risk factor of CVD in psoriatic patients. High serum chemerin levels are associated with recent-onset psoriasis rather than with long-standing disease, suggesting a possible role in the initiation of the disease. Moreover, the presence of MetS in psoriasis patients is closely related to the severity of the disease.
Conflicts of interest
There are no conflicts of interest.
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