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ORIGINAL ARTICLE Table of Contents  
Ahead of print publication
Diosmetin ameliorates imiquimod-induced psoriasis by regulating apoptosis and inflammation via toll-like receptor 4/nuclear factor kappa B pathway


1 Department of Dermatology, The Second Affiliated Hospital of Xinjiang Medical University, Urumqi, China
2 Department of Dermatology, The Fifth Affiliated Hospital of Xinjiang Medical University, Urumqi, China

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Date of Submission16-Aug-2021
Date of Decision17-May-2022
Date of Acceptance25-May-2022
Date of Web Publication06-Oct-2022
 

  Abstract 


Background: Psoriasis is a common skin inflammatory disease. Dysregulated growth and differentiation of keratinocytes are the main characteristics of psoriasis. Diosmetin is a naturally occurring flavonoid with antioxidant, anti-inflammatory, and antibacterial properties. However, the anti-psoriatic role and mechanism of diosmetin remain unclear. Objectives: To investigate anti-psoriatic role and mechanism of diosmetin. Methods: Human immortalized epidermal cells (HaCaT) were treated with tumor necrosis factor-alpha (TNF-α) to establish the cell model of psoriasis. Mice were treated with imiquimod (IMQ) to establish the animal model of psoriasis. Cell viability and apoptosis were detected by methyl thiazolyl tetrazolium and flow cytometry, respectively. Reverse transcription-quantitative polymerase chain reaction and ELISA assays were performed to detect the expression of interleukin (IL)-6 and IL-8. Hematoxylin and eosin staining was used to detect the skin lesion. Results: Diosmetin reduced cell viability and promoted the apoptosis of TNF-α-induced HaCaT. Protein expression of Bax in TNF-α-induced HaCaT was up-regulated, while Bcl-2 was down-regulated by diosmetin. Diosmetin attenuated TNF-α-induced increase in IL-6 and IL-8 in HaCaT. The enhanced protein expression of toll-like receptor 4 (TLR 4) (toll-like receptor 4), p65 and IκBα phosphorylation, as well as reduced IκBα in TNF-α-induced HaCaT were restored by diosmetin. Diosmetin improved IMQ-induced skin lesion and attenuated inflammatory response in psoriasis-like mouse model. Conclusion: Diosmetin exerted anti-inflammatory and pro-apoptotic effects on TNF-α-induced HaCaT and IMQ-induced mice through inactivation of TLR4/nuclear factor kappa B pathway.

Keywords: Apoptosis, diosmetin, hacat, imiquimod, inflammation, proliferation, toll-like receptor 4/nuclear factor kappa B, tumor necrosis factor-alpha


How to cite this URL:
Yang J, Zhan M, Chen Z, Li L, Lu J, Yang M, Gao X. Diosmetin ameliorates imiquimod-induced psoriasis by regulating apoptosis and inflammation via toll-like receptor 4/nuclear factor kappa B pathway. Dermatol Sin [Epub ahead of print] [cited 2022 Nov 28]. Available from: https://www.dermsinica.org/preprintarticle.asp?id=357998





  Introduction Top


Psoriasis is a chronic immune-associated skin disease caused by genetic, epigenetic and environmental factors and is one of the autoimmune inflammatory diseases.[1] The histological features of psoriasis are hyperplasia of the epidermis, dedifferentiation of keratinocytes, marked dilation of blood vessels, and infiltration of inflammatory cells around the capillaries of the dermis.[2] Therapeutic strategies, including Vitamin D analogues, corticosteroids, calcineurin inhibitors and topical retinoid, have been used for the amelioration of psoriasis, and novel treatments are needed to improve the efficacy.[3]

The pathogenesis of psoriasis is complicated, including metabolic disorders, genetic and environmental factors, and its specific mechanism is still unclear.[4] Keratinocyte hyperproliferation contributes to the production of pro-inflammatory cytokines, and the released cytokines amplify the local immune response by forming a positive feedback loop, thus resulting in maintaining the persistence of psoriatic lesions.[5] Therefore, reagents that inhibit proliferation and inflammatory response, and induce apoptosis of keratinocytes are considered to be an effective strategy in the treatment of psoriasis.[6]

Diosmetin, a biological flavonoid isolated from the leaves of Olea europaea L, has been found to exert anti-inflammatory, anti-oxidation, anti-tumor, and antiviral activities.[7],[8] For example, diosmetin suppressed endotoxin-induced acute hepatic failure through anti-inflammatory and anti-oxidative abilities.[9] Diosmetin promoted cell apoptosis of liver carcinoma cells[10] and suppressed cell proliferation and inflammatory response of tumor necrosis factor-alpha (TNF-α)-induced human rheumatoid arthritis fibroblast-like synoviocytes (MH7A).[11] Lipopolysaccharide and IL-4-induced atopic dermatitis and macrophage activation were also repressed by diosmetin.[12] However, few studies have been reported about the effects of diosmetin on psoriasis.

The present study was performed to investigate the effects of diosmetin on cell proliferation, apoptosis, and inflammation of in vitro cell model of psoriasis. Effects of diosmetin on imiquimod (IMQ)-induced mice were also evaluated. In addition, the related mechanism involved in anti-apoptotic and anti-inflammatory effects of diosmetin on psoriasis were also investigated in this study.


  Materials and Methods Top


Cell culture and treatment

Human immortalized epidermal cells (HaCaT) were purchased from Cell Culture Unit of Shanghai Science Academy (Shanghai, China). Cells were cultured in minimal essential media medium containing 10% fetal bovine serum and penicillin-streptomycin (Gibco Life Technologies, Carlsbad, CA, USA) at a 37°C incubator. For establishment of psoriasis cell model, cells were treated with 10 ng/mL TNF-α (Sigma-Aldrich, St. Louis, MI, USA) for 12 h. TNF-α-induced HaCaT were then incubated with 5, 10, or 20 μM diosmetin (PureOne Biotechnology, Shanghai, China) for another 24 h.

Cell viability and apoptosis

HaCaT was seeded into a 96-well plate and incubated with TNF-α for 12 h, followed by incubation with diosmetin for another 24 h. Methyl thiazolyl tetrazolium (MTT) solution (Dojindo, Kumamoto, Japan) was added into each well and incubated for 4 h. Following incubation with dimethyl sulfoxide (Fluka, Buchs, Switzerland), the absorbance at 490 nm was measured by microplate reader (Thermo Labsystems, Helsinki, Finland). For cell apoptosis, TNF-α-induced HaCaT cells with or without diosmetin incubation were harvested and suspended in 100 μL of annexin-V binding buffer from Annexin V-fluorescein isothiocyanate (V-FITC) Apoptosis Detection Kit (Sigma-Aldrich). Following incubation with 10 μL FITC-conjugated annexin V and 10 μL PI, the cells were analyzed by fluorescence-activated cell sorting Calibur flow cytometer (BD Biosciences, SanJose, CA, USA).

Caspase activity and ELISA

HaCaT was lysed in radioimmunoprecipitation assay lysis buffer (Sigma-Aldrich), and the protein concentration was quantified by QuantiPro™ BCA Assay Kit (Sigma-Aldrich). The supernatants were collected and then conducted with caspase-3 or caspase-9 activity assay kits (Beyotime, Beijing, China) or commercial ELISA kits (Beyotime) to determine the levels of Interleukin (IL)-6 and IL-8. Levels of IL-6 and IL-8 in skin samples from mice were also determined by the commercial ELISA kits (Beyotime).

Real-time polymerase chain reaction

Total RNAs in HaCaT cells and skin samples were isolated using Trizol reagent (Sigma-Aldrich) and then reverse-transcribed into cDNAs. SYBR Premix Ex Taq II (Takara, Shiga, Japan) was used for the Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis of IL-6 and IL-8 with following primers: IL-6 (forward 5'-AAGCCAGAGCTGTGCAGATGAGTA-3'; reverse 5'-TGTCCTGCAGCCACTGGTTC-3'), IL-8 (forward 5'-GGTGCAGTTTTGCCAAGGAG-3'; reverse 5'-TTCCTTGGGGTCCAGACAGA-3') and GAPDH (forward 5'-TGTGGGCATCAATGGATTTGG-3'; reverse 5'-ACACCATGTATTCCGGGTCAAT-3'). Conditions: 95°C for 15 s, 35 cycles of 95°C for 5 s and 61°C for 15 seconds, were used for the PCR reaction. The relative mRNA expression of IL-6 and IL-8 was normalized to the GAPDH by the 2ΔΔCt method.

Western blot

Proteins isolated from HaCaT were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and then transferred onto Polyvinylidene fluoride membrane (Millipore, Billerica, MA, USA). The membranes were incubated with blocking solution (TBST buffer containing 5% skimmed milk powder and 0.05% Tween 20), and then probed with primary antibodies: anti-Bax and anti-Bcl-2 (1:2000; Abcam, Cambridge, UK), anti-Toll-like receptor 4 (TLR4) and anti-GAPDH (1:3000; Abcam), anti-p65 and anti-p-p65 (1:3500; Abcam), anti-IκBα and anti-p-IκBα (1:4000; Abcam). The membranes were incubated with horseradish peroxidase-conjugated anti-IgG secondary antibody (1:5000; Abcam) and enhanced chemiluminescence (Pierce, Rockford, IL, USA) was used to measure the blots.

Animal experiments

A total of 15 BALB/c mice (6–8 weeks old, 20–22 g weight) were acquired from Hunan SJA Laboratory Animal Co., Ltd. (Hunan, China). Mice were kept in controlled conditions with free access to food and water. Ethical approval was obtained from the Ethics Committee of the Second Affiliated Hospital of Xinjiang Medical University (Approval No.20200314-06). Mice were randomly divided into three groups: control (N = 5), (IMQ, N = 5), and IMQ with diosmetin (N = 5). Mice in the control group were treated with 62.5 mg vaseline daily on the back skin for 1 week. Mice in the IMQ group were treated with 62.5 mg of IMQ cream (Sigma-Aldrich) for 1 week. Mice in the IMQ with diosmetin and IMQ groups were treated with 5 mg/kg per day cream and vehicle cream, respectively, for another 1 week. Psoriasis Area Severity Index (PASI) scores were recorded on the 8th day from 0 to 4: 0, none; 1, 2, moderate; 3, severe; 4, very severe. The mice were then euthanized to collect the skin samples for histological, qRT-PCR, and ELISA analysis.

Histological analysis

The skin samples were isolated from the mice and then fixed in 4% paraformaldehyde. The tissues were embedded in paraffin and sectioned into 4 μm sections. The sections were stained with hematoxylin and eosin (Sigma-Aldrich) for histological evaluation.

Statistical analyses

All the results, obtained from triplicate parallel experiments, were expressed as means ± SD SPSS 16.0 software (SPSS Inc., Chicago, IL, USA) was used to perform the statistical analyses. The significance levels were determined by Student's t-test and one-way Analysis of Variance. P < 0.05 was considered statistically significant.


  Results Top


Diosmetin repressed cell viability of tumor necrosis factor-alpha induced human immortalized epidermal cells

To establish the cell model of psoriasis, HaCaT was treated with 10 ng/mL TNF-α. TNF-α-induced HaCaT cells were then incubated with diosmetin. Flow cytometry analysis showed that diosmetin more than 40 μM (80, 100 or 200 μM) promoted cell apoptosis of HaCaT [Figure 1]a. MTT analysis showed that TNF-α increased the cell viability of HaCaT [Figure 1]b. Incubation with diosmetin, in a dosage-dependent way, decreased the cell viability of TNF-α-induced HaCaT [Figure 1]b, suggesting the anti-proliferative effect of diosmetin on psoriasis.
Figure 1: Diosmetin repressed cell viability of TNF-α-induced HaCaT, (a) Diosmetin more than 40 μM (80, 100 or 200 μM) promoted cell apoptosis of HaCaT, (b) Diosmetin, in a dosage dependent way, decreased the cell viability of TNF-α-induced HaCaT. *P < 0.05, **P < 0.01, HaCaT: Human immortalized epidermal cells, TNF-α: tumor necrosis factor-alpha

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Diosmetin promoted cell apoptosis of tumor necrosis factor-alpha induced human immortalized epidermal cells

Although TNF-α has no significant effect on cell apoptosis of HaCaT, diosmetin at concentrations of 10, or 20 μM dramatically promoted the cell apoptosis of TNF-α-induced HaCaT [Figure 2]a. Protein expression of Bax in TNF-α-induced HaCaT was up-regulated, while Bcl-2 was down regulated by diosmetin at concentrations of 10, or 20 μM [Figure 2]b. Moreover, diosmetin at a concentration of 10 or 20 μM promoted the activities of caspase-3 and caspase-9 in TNF-α-induced HaCaT [Figure 2]c, suggesting the pro-apoptotic effect of diosmetin on psoriasis.
Figure 2: Diosmetin repressed cell apoptosis of TNF-α-induced HaCaT, (a) Diosmetin, in a dosage dependent way, promoted the cell apoptosis of TNF-α-induced HaCaT using Annexin V-FITC Apoptosis Detection Kit. (b) Diosmetin, in a dosage dependent way, enhanced protein expression of Bax and reduced Bcl-2 in TNF-α-induced HaCaT. (c) Diosmetin, in a dosage dependent way, enhanced activities of caspase-3 and caspase-9 in TNF-α-induced HaCaT. *P < 0.05, **P < 0.01. HaCaT: Human immortalized epidermal cells, TNF-α: tumor necrosis factor-alpha, V-FITC: V-fluorescein isothiocyanate

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Diosmetin repressed inflammatory response of tumor necrosis factor-alpha induced human immortalized epidermal cells

The effect of diosmetin on inflammation of TNF-α-induced HaCaT was investigated by RT-PCR and ELISA assay. The results by RT-qPCR [Figure 3]a and ELISA [Figure 3]b showed that diosmetin at a concentration of 10 or 20 μM attenuated TNF-α-induced increase in IL-6 and IL-8 in HaCaT, suggesting the anti-inflammatory effect of diosmetin on psoriasis.
Figure 3: Diosmetin repressed inflammatory response of TNF-α-induced HaCaT. (a) Diosmetin, in a dosage dependent way, reduced mRNA expression of IL-6 and IL-8 in TNF-α-induced HaCaT.(b) Diosmetin, in a dosage dependent way, reduced protein expression of IL-6 and IL-8 in TNF-α-induced HaCaT. *P < 0.05, **P < 0.01, HaCaT: Human immortalized epidermal cells, TNF-α: tumor necrosis factor-alpha

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Diosmetin repressed activation of toll-like receptor 4/nuclear factor kappa B pathway in tumor necrosis factor-alpha induced human immortalized epidermal cells

Protein expression of TLR4 was enhanced in TNF-α-induced HaCaT [Figure 4], whereas reduced by diosmetin incubation [Figure 4]. Diosmetin also attenuated TNF-α-induced increase in p65 phosphorylation in HaCaT [Figure 4]. Moreover, TNF-α-induced increase in IκBα phosphorylation and decrease in IκBα in HaCaT were restored by diosmetin [Figure 4], suggesting that diosmetin repressed activation of TLR4/Nuclear factor kappa B (NF-κB) pathway in TNF-α-induced HaCaT.
Figure 4: Diosmetin repressed activation of TLR4/NF-κB pathway in TNF-α-induced HaCaT, Diosmetin, in a dosage dependent way, enhanced IκBα and reduced protein expression of TLR4, p-p65, p-IκBα in TNF-α-induced HaCaT. **P < 0.01, HaCaT: Human immortalized epidermal cells, TNF-α: tumor necrosis factor-alpha, TLR4/NF-κB: Toll-like receptor 4/NF-κB

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Diosmetin ameliorated imiquimod induced psoriasis-like skin lesion in mice

IMQ was applied to establish psoriasis-like skin lesion model in mice. Analysis of structural features showed that IMQ induced symptoms of thickening, erythema and scaling in the skin lesions compared to the control [Figure 5]a, as demonstrated by increased PASI score [Figure 5]a. However, treatment with diosmetin ameliorated the pathological changes and reduced the PASI score [Figure 5]a. Moreover, histopathological analysis showed that IMQ also induced skin lesion in mice, as demonstrated by thicker epidermal layers, incomplete keratosis, hyperkeratosis, hyperemia and dilation of capillaries in dermis, and inflammatory cell infiltration [Figure 5]b. However, treatment with diosmetin reduced the epidermal thickness [Figure 5]b. Treatment with diosmetin also attenuated IMQ-induced increase in IL-6 and IL-8 expression in mice [Figure 5]c and [Figure 5]d. In addition, diosmetin reduced protein expression of Bcl-2 and enhanced the level of Bax and cleaved caspase-3 in IMQ-induced mice [Figure 5]e suggesting that diosmetin exerted pro-apoptotic and anti-inflammatory effects against psoriasis
Figure 5: Diosmetin ameliorated IMQ-induced psoriasis-like skin lesion in mice (a) Diosmetin ameliorated the pathological changes in skin lesions of IMQ-induced mice, and attenuated IMQ-induced increase of PASI score in mice. (b) Diosmetin ameliorated histopathological analysis in IMQ-induced mice. (c) Diosmetin attenuated IMQ-induced increase of IL-6 and IL-8 mRNA expression in mice. (d) Diosmetin attenuated IMQ-induced increase of IL-6 and IL-8 protein expression in mice. (e) Diosmetin reduced protein expression of Bcl-2, and enhanced Bax and cleaved caspase-3 in IMQ-induced mice. ** P < 0.01. IMQ: Imiquimod

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  Discussion Top


Flavonoids, isolated from traditionally plants, are widely used in the prevention of dermatologic disorders, including psoriasis.[13] For example, formononetin-7-O-β-D-glucoside, quercetin-3-O-β-D-glucuronide and luteolin-7-O-β- glucopyranoside are flavonoids isolated from the plant Cassia tora L., Fabaceae, and possess anti-psoriatic activity in ultraviolet B ray-induced photodermatitis rats model.[14] Flavonoid, quercetin, also suppressed IMQ-induced inflammation of psoriasis.[15] Considering the anti-inflammatory effect of diosmetin on IL-4-induced atopic dermatitis[12] and TNF-α-induced MH7A,[11] the anti-psoriatic activity of diosmetin was investigated in this study.

Hyperproliferation of keratinocyte is implicated in the pathogenesis of psoriasis. TNF-α has been shown to increase cell proliferation of HaCaT, and TNF-α-induced HaCaT was used as an in vitro cell model of psoriasis.[16] This study also establish cell model of psoriasis through incubation of HaCaT with TNF-α, and the cell viability of HaCaT was promoted by TNF-α. TNF-α induced cell proliferation of MH7A was suppressed by diosmetin.[11] This study also confirmed that diosmetin reduced cell viability of TNF-α-induced HaCaT, suggesting the anti-proliferative effect against psoriasis. Moreover, the cell apoptosis of TNF-α-induced HaCaT and IMQ-induced mice was promoted by diosmetin, confirming the pro-apoptotic effect of diosmetin on psoriasis.

The interplay of pro-inflammatory cytokines and immune cells is also implicated in the pathogenesis of psoriasis.[17] Active psoriatic patients demonstrated higher levels of IL-6 and IL-8 than the controls.[18] TNF-α-induced increase in proinflammatory factors, IL-6 and IL-8, in HaCaT, and suppression of the inflammation exerted anti-psoriasis effect against psoriasis.[19] Consistent with previous study that diosmetin attenuated TNF-α-induced increase in IL-6 and IL-8 in MH7A cells,[11] our results showed that the enhanced levels of IL-6 and IL-8 in TNF-α-induced HaCaT were reduced by diosmetin. Moreover, diosmetin also reduced levels of IL-6 and IL-8 in IMQ-induced mice, suggesting the anti-inflammatory effect of diosmetin on psoriasis. Additionally, oxidative stress has been shown to contribute to the abnormal hyperproliferation and differentiation of keratinocytes, thus participating in the development of psoriasis.[20] Since diosmetin exerted anti-oxidative effect against endotoxin-induced acute hepatic failure,[9] the role of diosmetin in oxidative stress of TNF-α-induced HaCaT should be investigated in further research.

NF-κB participates in many biological processes, such as inflammation, cell apoptosis, and tumorigenesis.[21] NF-κB has been reported to be a critical connector between the immune cell behavior and altered keratinocyte proliferation, thereby characterizing the psoriatic milieu.[21] TLR4 functions as a pattern recognition receptor to stimulate the production of numerous pro-inflammatory cytokines by the activation of NF-κB pathway.[22] In psoriasis, activation of TLR4 promoted the nuclear translocation of NF-κB and enhanced the expression of IL-1 β and IL-6.[23] The suppression of TLR4/NF-κB activation alleviated disease progression of psoriasis.[23] Diosmetin suppressed activation of NF-κB pathway to retard neuronal apoptosis and inflammation[24] and attenuated cerulein-induced acute pancreatitis through inactivation of NF-κB pathway.[25] Moreover, TNF-α-induced proliferation and inflammation of MH7A were repressed by diosmetin through inhibition of NF-κB pathway.[11] The result in this study showed that protein expression of p65 phosphorylation and TLR4 were enhanced, and NF-κB inhibitor, IκBα, was reduced in TNF-α-induced HaCaT. Diosmetin reduced phosphorylation of IκBα and enhanced IκBα to decrease protein expression of p65 phosphorylation and TLR4, demonstrating that diosmetin suppressed activation of TLR4/NF-κB pathway in TNF-α-induced HaCaT.


  Conclusion Top


Diosmetin promoted cell apoptosis and suppressed proliferation and inflammation of TNF-α-induced HaCaT in a dosage-dependent way. Furthermore, diosmetin also promoted cell apoptosis and inhibited inflammation in IMQ-induced mice, providing

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Correspondence Address:
Jinyan Yang,
Department of Dermatology, The Second Affiliated Hospital of Xinjiang Medical University, No. 38, Nanhu East Road, Shuimogou District, Xinjiang Uygur Autonomous Region
China
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ds.ds_31_22



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