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Erschienen in: Chinese Medicine 1/2024

Open Access 01.12.2024 | Research

Traditional Chinese Medicine Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation

verfasst von: Chenyang Zhang, Xinran Cao, Lixin Zhao, Zitong Ni, Haojie Du, Jiao Qu, Jianxia Zhu, Haiyan Sun, Yang Sun, Zijun Ouyang

Erschienen in: Chinese Medicine | Ausgabe 1/2024

Abstract

Background

Psoriasis is a chronic inflammatory genetic disease, mainly manifesting in the skin. Conventional therapies, such as glucocorticosteroids and corticosteroids, have adverse effects that limit drug use. Hence, it is imperative to identify a new therapeutic strategy that exhibits a favorable safety profile. Shi-Bi-Man (SBM) is a safe herbal supplement sourced from various natural plants, including ginseng, angelica sinensis, polygonum multiflorum, and aloe vera.

Purpose

We aimed to find a potential treatment for psoriasis and investigate the underlying mechanism through which SBM alleviates psoriatic-like skin inflammation in mice.

Methods

We investigated the effects of supplementing with SBM through intragastric administration or smear administration in a murine model of imiquimod-induced psoriasis. The changes in body weight and Psoriasis Area and Severity Index (PASI) score were recorded throughout the entire process. Additionally, we used hematoxylin–eosin staining to observe the skin structure and performed single-cell RNA sequencing to explore the underlying mechanism of SBM in influencing the psoriasis-like phenotype. Immunofluorescence was conducted to verify our findings. Furthermore, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was employed to investigate the impact of Tetrahydroxy stilbene glycoside (TSG) on the expression levels of IL23 in HaCaT cells.

Results

SBM remarkably alleviated the psoriasis-like phenotype by inhibiting IL-23/Th17 cell axis. Single-cell RNA sequencing analysis revealed a decrease in the expression of Il17 and Il23 in keratinocytes and T cells, concomitant with a reduction in the proportion of Th17 cells. Meanwhile, the activation of endothelial cells was inhibited, accompanied by a decrease in the expression of Cxcl16. In vitro, the addition of TSG to HaCaT cells resulted in significant suppression of IL23 expression stimulated by tumor necrosis factor-alpha (TNF-α).
Hinweise
Chenyang Zhang and Xinran Cao have contributed equally to this work.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Abkürzungen
EGCG
Epigallocatechin gallate
FGF
Fibroblast growth factor
GO
Gene ontology
IMQ
Imiquimod cream
PASI
Psoriasis area and severity index
RT-qPCR
Reverse transcription-quantitative polymerase chain reaction
SBM
Shi-Bi-Man
TNF-α
Tumor necrosis factor-alpha
TSG
Tetrahydroxy stilbene glycoside
UMAP
Uniform manifold approximation and projection
VEGF
Vascular endothelial growth factor

Introduction

Psoriasis is a chronic autoimmune skin disease characterized by plaques and scales [1]. The global prevalence is approximately 2% [2]. Despite chronic plaque-type psoriasis, which accounts for about 90% of psoriasis cases, some patients suffer from pustular psoriasis, guttate psoriasis, and inverse psoriasis [3]. Patients with psoriasis have excessive proliferation of keratinocytes, dilation of dermal capillaries, and infiltration of inflammatory cells. Patients afflicted with severe psoriasis experience a range of complications, such as the development of arthritis and immune dysfunction [4]. Dendritic cells and macrophages present in the dermis affected by psoriasis are responsible for the production of interleukin 23. This production leads to the activation of T cells, as well as the release of inflammatory cytokines including IL-17A, IL-17F, IL-22, IL-6, and TNF-α [5]. Small molecule inhibitors and biologics are commonly used in the clinical treatment of psoriasis. In certain case series, the surgical procedure of tonsillectomy has been found to result in a notable amelioration of plaque psoriasis [68]. Methotrexate and cyclosporine are widely used in the clinical management of psoriasis. Acitretin is used to inhibit the proliferation and differentiation of keratinocytes [9, 10]. Nevertheless, the attainment of long-term usage is challenging due to the adverse effects and the potential for relapse following cessation [11]. T cells play a pivotal role in mediating various inflammation and immune disorders. T cell-based immunotherapy is advancing. CXC chemokine receptor 6 (CXCR6) has been listed a novel target for immunotherapy for autoimmune, including psoriasis. [12] With the approval of the Etanercept for clinical use by the U.S. Food and Drug Administration, the advent of biologic therapies for psoriasis commenced. Subsequently, the discovery of the IL-23/Th17 axis has led to the development of a growing number of inhibitors that target IL-17 or IL-23, including guselkumab, which have entered the market [13]. Biologic medications, while exhibiting a reduced incidence of adverse effects, impose a significant economic strain on patients due to their exorbitant cost [14]. Hence, it holds clinical importance to identify a treatment that is both safe, efficacious and economically accessible.
As the study of psoriasis has advanced, there has been an increasing recognition of the significant involvement of endothelial cells in the progression of the disease. The characteristic epidermal hyperplasia observed in psoriasis is closely associated with the angiogenic microenvironment influenced by vascular endothelial growth factor (VEGF) [1]. Nonetheless, in another research, psoriasis has been linked to the genetic mutation of VEGF [15]. In addition, suppression of gene expression has been shown to effectively alleviate psoriasis-like features in a mouse model [16]. Furthermore, for psoriatic skin, endothelial cells become activated and release endothelial adhesion molecules, resulting in the recruitment of leukocytes and subsequent initiation of an inflammatory response [17].
As a blend of a variety of Chinese herbs, Shi-Bi-Man (SBM) comprises ingredients such as Radix Ginseng, tea polyphenols, Radix Polygoni Multiflori (the root tuber of Polygonum multiflorum Thunb.), Radix Angelica Sinensis from the root of Angelica sinensis (Oliv.) Diels, Aloe vera L., linseed, and green tea extract. SBM showed no toxicity in a prior mouse model [18]. Previous research has demonstrated that TSG and EGCG, the primary active components found in SBM, can stimulate hair regrowth by activating the fibroblast growth factor (FGF) pathway in dermal papillary cells [18].
In this study, we aimed to explain the mechanism of SBM in the treatment of psoriasis using single-cell sequencing technology, clarify the target of SBM based on specific cell populations, offering insights that could potentially introduce a new choice for the clinical treatment of psoriasis.

Materials and methods

Reagents

Imiquimod (GTH110C, 3 M Health Care Limited, UK) was purchased from Jiangsu Provincial Hospital of Traditional Chinese Medicine. Shi-Bi-Man (SBM) was purchased from Sipimo Biotechnology Co., Ltd (Shenzhen, China). TSG was purchased from Chengdu Purifa Technology Development Co., Ltd. TNF-α was purchased from MedChemExpress USA. Benvitimod was purchased from guanhaobio (Guangdong, China).

Mice

Six–Eight weeks-old female C57BL/6 mice (2023 g) were purchased from GemPharmatech Co., Ltd (Nanjing, China). The mice were kept in a controlled environment with a 12-h light/dark cycle at a temperature of 25 ± 1 ℃. They were provided with a standard laboratory diet and water ad libitum. The procedures described in this study were approved by the Experimental Animal Care and Use Committee of Nanjing University, by the guidelines outlined in the Guide for the Care and Use of Laboratory Animals (IACUC-2306011).

Imiquimod-induced model of psoriasis and SBM treatment

After anesthesia with 1% pentobarbital sodium by intraperitoneal injection, the hair on the back of the mice was shaved. A total of 30 mice were divided into six groups: (1) vehicle group; (2) IMQ group; (3) IMQ + benvitimod group; (4) IMQ + SBM group (skin administration; SBM:200 μL, daily for 5 consecutive days); (5) IMQ + 20 mg/kg SBM group (i.g. SBM, daily for 5 consecutive days); (6) IMQ + 40 mg/kg SBM group (i.g. SBM, daily for 5 consecutive days). The vehicle group was treated with glycerol. For the establishment of psoriasis mouse model, mice were topically treated with 62.5 mg 5% IMQ cream on shaved back skin daily for 5 consecutive days. Benvitimod were skin administrated 62.5 mg daily for 5 consecutive days. SBM was dissolved in ddH2O containing 5% ethanol.

Histopathologic assessment

Mouse skin tissue was cut into 5 μm thick pieces. Paraffin sections were successively treated with xylene and ethanol according to the protocol of the hematoxylin–eosin staining kit (G1005, Servicebio, China), and after treatment with hematoxylin solution, eosin staining was used. Neutral balm was used to seal the slides.

Immunofluorescence

Immunofluorescence staining was performed on tissue and cell samples. For tissue samples, slides were deparaffinized, rehydrated, and treated with sodium citrate buffer for antigen retrieval. Slides were incubated with 3% goat serum for 30 min followed by primary antibodies: CXCL16 antibody (DF13312, Affinity Biosciences, China), VCAM1 antibody (DF6082, Affinity Biosciences, China), SELE/CD62E antibody (DF6914, Affinity Biosciences, China), IL-23A antibody (DF13760, Affinity Biosciences, China), IL-17A Polyclonal antibody (26163-1-AP, PTG, China), Purified anti-human/mouse CD3ε (362701, Biolegend, USA), CD31 antibody (ab134168, Abcam, USA), Anti-E Cadherin antibody (ab231303, Abcam, USA). The secondary antibody used were Goat anti-Rabbit IgG (H + L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 488 (A-11008, Invitrogen), Goat anti-Mouse IgG (H + L) Cross-Adsorbed Secondary Antibody, Alexa Fluor™ 594 (A-11005, Invitrogen).

Realtime-quantitative polymerase chain reaction (RT-qPCR)

TRIzol reagent (Takara, Cat. #9109) was used for total mRNA isolation. We synthesized cDNA using iScript Reverse Transcription Supermix (Bio-Rad), and BioRad CFX96 ouch™ Real-Time PCR Detection System (BioRad, CA, USA) was used for quantitative RT-PCR. HiScript II Q RT SuperMix for qPCR (R223-01) and Taq Pro Universal SYBR qPCR Master Mix (Q712-02) were purchased from Vazyme. Relative gene expression was calculated as 2^−△△Ct, where Gapdh was used as the housekeeping gene for normalization.
Detailed information about the primers for mice used is listed below:
Gapdh, 5′-AGGTCGGTGTGAACGGATTTG-3′ (forward)
5′-GGGGTCGTTGATGGCAACA-3′ (reverse);
l17f, 5′-TGCTACTGTTGATGTTGGGAC-3′ (forward)
5′-CAGAAATGCCCTGGTTTTGGT-3′ (reverse);
Il23, 5′-ATGAGTTTTTCCCTTATGGGGAC-3′ (forward)
5′-GCTGGAAGTTGGACACCTCAA-3′ (reverse);
Detailed information about the primers for HaCaT cells used is listed below:
GAPDH, 5’-GGAGCGAGATCCCTCCAAAAT (forward)
5’-GGCTGTTGTCATACTTCTCATGG (reverse);
TNF-α, 5′- CCTCTCTCTAATCAGCCCTCTG-3′ (forward)
5′- GAGGACCTGGGAGTAGATGAG-3′ (reverse);
IL23, 5′- CTCAGGGACAACAGTCAGTTC-3′ (forward)
5′- ACAGGGCTATCAGGGAGCA-3′ (reverse);

Scoring severity of skin inflammation

The clinical PASI was applied to evaluate the progression of psoriasis in mice. According to the PASI scoring standard, erythema, scaling, and thickening were taken into account, each ranging from 0 to 4. 0, none; 1, slight; 2, moderate; 3, significant; 4, extremely significant.

Single-cell RNA-seq

Skin tissues were collected after euthanasia of the mice and rinsed with phosphate-buffered saline (PBS) thrice. Subsequently, the tissues were sectioned into smaller pieces and digested into single-cell suspensions using collagenase I (Sigma), collagenase II (Sigma), and Dispase® (Sigma).
The suspension was loaded into microfluidic devices using the Singleron Matrix® Single Cell Processing System (Singleron). The scRNA-seq library was constructed according to the protocol of the GEXSCOPE® Single Cell RNA Library Kit (Singleron). The pools were sequenced on a NovaSeq 6000 system (Illumina, USA). The data were uploaded to the GEO database.
To process the raw data and convert it into a matrix suitable for analysis in R, the CeleScope package (v 1.13.0) was employed. The Seurat package (v3.2.3) in R was used for data analysis. Cells were filtered based on gene expression levels, with a threshold of more than 3000 and less than 300 genes. Additionally, cells with mitochondrial reads exceeding 8% and cells with unique molecular identifier (UMI) counts below 800 were excluded. The 'vst' method was used to integrate the data to remove the batch effect. The RunPCA function was used for dimension reduction. We used the uniform manifold approximation and projection (UMAP) function and the FindAllMarkers function. The top 30 genes scored by log2 fold-change were used for cell definition. The R package CellChat (v 1.5.0) was used for cell–cell communication analysis.

Cell culture and treatment

The HaCaT cell line was procured from the BeNa Culture Collection in Suzhou, China. The cells were maintained in Dulbecco's Modified Eagle Medium (DMEM) supplemented with 10% fetal bovine serum and 1% streptomycin-penicillin solution. The cells were incubated in a humidified environment at 37 °C with 5% CO2. To induce cellular response, the HaCaT cells were treated with 50 ng/mL of TNF-α and 5 μM of TSG for a duration of 24 h.

Spectrum analysis

TSG and ginsenoside Rd were purchased from Chengdu Purifa Technology Development Co., Ltd. and were compared with quality scores greater than 98%.
Chromatographic conditions (qualitative) were as follows. LC-40D liquid chromatograph (SHIMADZHU, Japan); Chromatographic column: Kinetex C18 colume (100 X 4.6 mm, 2.6 μm, Phenomenex, USA).
The injection volume was 5 µL using a mobile phase system with mobile phase flow rate of 0.6 mL/min and column temperature of 40 ℃. The mobile phase were (A) 0.025% formic acid water aqueous solution, (B) methanol–acetonitrile (containing 0.025% formic acid) mixture (50:50, v/v). The gradient elution procedure was as follows: 0–2 min, A: 95%; 2–35 min, A: 95–5%; 35–45 min, A: 5%; 45–46 min, A: 5–95%; 46–50 min, A: 95%.
The mass spectrometry conditions were as follows: Acetonitrile, methanol, and formic acid were chromatographically pure (MERCK company), the water was ultrapure water (obtained by Millipore Milli-Q Synthesis System). Electrospray ion source (ESI) negative ion scanning mode was adopted. The gas temperature was maintained at 550 ℃; The curtain gas was set at 35 psi. CAD gas was 7. The spray voltage was set as 4500 V. Declustering potential was set at 80 V and collision energy at 10 V. TOF Mass range was set at m/z 50–1500 Da. All data were collected and processed using an UPLC-Q-TOF-MS/MS (SCIEX Zeno TOF 7600, USA).

Statistical analysis

GraphPad Prism 8 (GraphPad, San Diego) was used for statistical analysis. One-way ANOVA with Tukey’s multiple comparisons and paired or unpaired Student’s t-test were applied. Differences at P < 0.05 was considered statistically significant (*P < 0.05, **P < 0.01), and ns represents no significance. All data are presented as the mean ± SEM.

Result

SBM relieves psoriasis-like phenotype in the mice model

To investigate the function of SBM in psoriasis, we applied it to the skin of mice. Benvitimod, which has been shown to have a good therapeutic effect on psoriasis, was used as a control drug [19]. Compared with the IMQ group, SBM alleviated the symptoms of psoriasis induced by IMQ (Fig. 1A). Epidermal thickness was reduced (Fig. 1A–C). The clinical PASI score of the IMQ + SBM group was significantly reduced compared to the IMQ group (Fig. 1B). The body weight (Fig. 1D). In addition, the expressions of inflammatory factors such as IL-17F, and IL-22 were significantly reduced after SBM treatment (Fig. 1E). Among them, the application of SBM solution was the most effective.

Single-cell RNA sequencing reveals the main skin cell types in mice

The single-cell RNA sequencing was performed on the skin tissues of mice. The 11 cell types revealed by unbiased clustering were identified as fibroblasts, keratinocytes, T cells, macrophages, stromal cells, endothelial cells, dermal papilla cells, dendritic cells (DC), melanocytes, smooth muscle cells, and sebaceous gland cells (Fig. 2A, B). The pie chart showed the percent of each cell type (Fig. 2A, B). The cell composition of each group was revealed by a stacked bar diagram (Fig. 2C). The expression of marker genes was presented by a violin diagram (Fig. 2D).

SBM significantly decreases the expression of psoriasis-related effector genes in keratinocytes

Keratinocytes play a crucial role in the pathogenesis and progression of psoriasis. In this study, we isolated and analyzed one keratinocyte subset (Fig. 3A). To identify effector genes which are involved in psoriasis, we used the GeneCards database. The expression of these genes in each group was visualized using a heatmap, with a relevance score threshold of over 20. Interestingly, we observed a downregulation of Il17a, Il17f and Il23a (Fig. 3B). Based on the expression levels of psoriasis-related genes, we categorized the keratinocytes into two groups: one with high expression and the other devoid of such expression. Following SBM treatment, we observed a reduction in the percentage of keratinocytes exhibiting high expression levels (Fig. 3C). Furthermore, a dotplot analysis revealed the top genes expressed in both keratinocyte groups (Fig. 3D).

SBM significantly reduces the infiltration of Th17 cells and inhibits the inflammatory response

The IL-23/Th17 axis has been proven to be the main mechanism of psoriasis pathogenesis in previous studies. We also found that Il17a, Il17f, and Il23a were downregulated in keratinocytes after SBM treatment. Thus, we conducted further analysis on T cells and defined the Th17 cells based on the expression levels of Il17a and Il17f (Fig. 4A–D). The percentage of Th17 cells decreased in the SBM group (Fig. 4C). Gene Ontology (GO) enrichment analysis of the top 100 genes evaluated by the fold change (FC) value (log2 FC > 1) with p-value < 0.05 showed that SBM treatment suppressed pathways related to inflammatory responses which were upregulated by IMQ (Fig. 4E).

SBM inhibits the IL-23/Th17 axis

Considering the reduction in the percentage of Th17 cells, we suspected that the IL-23/Th17 axis was suppressed. By analyzing the differentially expressed genes, we found that SBM remarkably reversed the upregulation of Il17a and Il17f (Fig. 5A). The related genes of the IL-23/Th17 axis were downregulated in both keratinocytes and T cells (Fig. 5B). Immunofluorescence confirmed that SBM suppressed IL-23/Th17 axis in psoriasis (Fig. 5C). The infiltration of Th17 was decreased, as shown in Fig. 5C. The keratinocytes expressed less IL-23, which can induce T cell express IL-17. And higher expression level of IL-17 can cause the proliferation of keratinocytes. However, after the expression of Il17 in T cell was also reduced in Fig. 5A, B. Thus, SBM suppressed IL-23/Th17 axis in psoriasis.

SBM suppresses endothelial cell activation in psoriasis

An increasing number of studies have confirmed the importance of endothelial cells in psoriasis [20]. SBM treatment downregulated proinflammatory cytokine genes such as Cxcl1, Il17a and Ecm1 (Fig. 6A). We performed GeneMANIA database analysis based on the 22 genes that were upregulated in the IMQ group and downregulated after SBM treatment (Fig. 6B, C). The function of endothelial cells to other immune cells was inhibited, such as myeloid leukocyte migration, cell chemotaxis, leukocyte migration, etc.

SBM inhibits the expression of Cxcl16 in endothelial cell

To find out the mechanism of SBM inhibition of endothelial cell activation, we used the R package CellChat to analyze cell–cell communication. Endothelial cells participated in the CXCL signaling network (Fig. 7A). In the IMQ group, keratinocytes expressed higher levels of Cxcl16, as well as the expression level of its receptor CXCR6 in endothelial cells. The situation was reversed after SBM treatment (Fig. 7B) and confirmed by immunofluorescence (Fig. 7C).

TSG can inhibit the expression of Il23 in HaCaT cells

As we have identified the main ingredients in the SBM solution previously, we aimed to verify whether TSG and ginsenoside Rd were included in our sample. The UPLC/MS results showed that SBM contained TSG and ginsenoside Rd, and the compound characterization details were shown (Fig. 8A–C). TSG is the major monomer enriched in mice skin after SBM administration [18]. To investigate whether TSG plays a role in psoriasis treatment, we stimulated HaCaT cells with 50 ng/mL TNF-α and 5 μM TSG for 24 h. TNF-α significantly improved the expression of inflammatory factors such as IL-23. However, this was reversed by TSG (Fig. 8D). Since IL-23 promotes infiltration of T cells that produce IL-17 and IL-22 [21], the reduction of IL23 can inhibit the infiltration of Th17. In addition, the production of IL-17 by Th17 can promote keratinocyte proliferation [22].
In conclusion, SBM alleviates the psoriasis-like phenotype by inhibiting the IL-23/Th17 axis and CXCL16-mediated endothelial activation (Fig. 9).

Discussion

Psoriasis, a chronic relapsing autoimmune skin disease, is influenced by various risk factors. These factors include obesity, dyslipidemia, hypertension, lifestyle choices, and certain medications [23]. Recent researches have established a consensus that the IL-23/Th17 axis plays a crucial role in the development of psoriasis [4, 24]. Despite the emergence of drugs targeting IL-17, further investigation into the underlying mechanisms of psoriasis is ongoing. The severity of psoriasis is associated with the expression of endothelial inflammatory transcripts [25]. Tumor necrosis factor (TNF)-α and other cytokines contribute to the creation of a pro-angiogenic microenvironment in psoriasis [26]. Consequently, VEGF has emerged as a promising therapeutic target for psoriasis [27]. Studies have also demonstrated that alterations in fatty acid metabolism can exacerbate the pathogenesis of psoriasis-like symptoms [28]. Additionally, lysophosphatidic acid, a simple phospholipid found in nature, has been implicated in the development of psoriasis [29]. Furthermore, SHP2 has been shown to exacerbate psoriasis-like skin inflammation in mice through processes such as NETosis or TLR7 activation [30, 31].
As research progresses, it has become evident that a comprehensive understanding of psoriasis pathogenesis necessitates a global perspective that considers the interplay between different cell types and even organs. With the development of research technology, single-cell sequencing technology has gradually entered into basic scientific research [32]. With the development of research technology, single-cell sequencing technology has gradually entered into basic scientific research [33]. Through sequencing technology, we were able to study the molecular mechanism of SBM treatment of psoriasis at the single-cell level and explore the interactions between cells. Based on the analysis results, we can further explore the underlying molecular mechanism of complex diseases and search for potential drugs.
In recent times, there has been a growing utilization of Traditional Chinese Medicine alongside biologics in the management of immune-related disorders [32]. This trend can be attributed to the adverse effects and exorbitant costs associated with biologics, particularly in the treatment of conditions such as psoriasis and other immune diseases. Notably, ginsenoside radix has demonstrated its efficacy in preventing lung injury through its anti-inflammatory and anti-oxidative properties [34]. Re-Du-Ning injection ameliorates radiation-induced pneumonitis and fibrosis [35], as well as lung injury induced by LPS [36]. What’s more, Traditional Chinese Medicine help treat insulin resistance [37]. Paeonol ameliorates endometrial hyperplasia in mice via ferroptosis [38]. The herbal formula also took part in the treatment of psoriasis [39]. Cycloastragenol inhibits NLRP3 inflammasome-mediated pyroptosis in macrophages to relieve imiquimod-induced psoriasis-like skin inflammation in mice [40]. As a mixture of a variety of Chinese herbs, SBM includes ginsenoside radix and has no toxicity using SBM in a mouse model [18]. TSG, the main component in the skin after applying SBM, has been found to have the ability to treat non-alcoholic fatty liver diseases [41]. Furthermore, TSG exhibits anti-aging properties in addition to its anti-inflammatory effects [42]. Therefore, we applied SBM to the IMQ-induced psoriasis-like phenotype mouse model to find a safe and cost-effective treatment for psoriasis patients.
Depending on the scRNA-seq analysis, the potential molecular mechanism of SBM in the treatment of psoriasis was explained. IL-23 induces Th17 cells to activate and release inflammatory cytokines, leading to the typical pathological changes of psoriatic epidermal hyperplasia [43]. The keratinocytes secreted less IL-23 after the treatment of SBM, which leads to less Infiltration of T cells that secrete IL-17 that promotes keratinocytes proliferation [22]. After the treatment of SBM, IL-23/Th17 axis was inhibited. Since IL-17 also promotes endothelial dysfunction, we analyzed the changes in endothelial cells and found the activation of endothelial cells was suppressed. Considering patients with psoriasis are at increased risk of cardiovascular disease, SBM may be beneficial for thrombosis [44]. Further research is needed for specific applications in vascular-related diseases.
The single-cell transcriptomics showed the T cells produce less IL-17 after SBM administration. IL-17 induces keratinocyte proliferation [22]. As shown by single-cell transcriptomics, the expression level of inflammatory factors in endothelial cells was decreased, which reflects the inhibition of endothelial activation. Through cell–cell communication analysis, we found the CXCL signaling network changed (Fig. 7A). In the IMQ group, keratinocytes expressed higher levels of Cxcl16, as well as the expression level of its receptor CXCR6 in endothelial cells, which reversed after SBM treatment (Fig. 7B) and confirmed by immunofluorescence (Fig. 7C). We suspected the higher expression of Cxcl16 in keratinocytes leads to the activation of endothelial cells. And psoriasis is associated with endothelial activation [45].

Discussion

In conclusion, our results report that SBM significantly alleviated the psoriatic skin inflammation induced by imiquimod in mice via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation. Thus, this work suggests the potential therapeutic value of SBM in patients with psoriasis.

Acknowledgements

This work was supported by National Key Research and Development Plan (2022YFC3500200, 2022YFC3500202), School-Level Scientific Research Project of Shenzhen Polytechnic University (No. 6021310023K), Lihu Talent Cultivation Program of Shenzhen Polytechnic University (No. LHRC20220408), School of Life Science (NJU)-Sipimo Joint Funds and Mountain-Climbing Talents Project of Nanjing University.

Declarations

The work was approved by the Experimental Animal Care and Use Committee of Nanjing University, by the guidelines outlined in the Guide for the Care and Use of Laboratory Animals (IACUC-2306011).

Competing interests

The authors have no competing interests to declare.
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Literatur
2.
Zurück zum Zitat Christophers E. Psoriasis–epidemiology and clinical spectrum. Clin Exp Dermatol. 2001;26(4):314–20.PubMedCrossRef Christophers E. Psoriasis–epidemiology and clinical spectrum. Clin Exp Dermatol. 2001;26(4):314–20.PubMedCrossRef
4.
Zurück zum Zitat Song C, Yang C, Meng S, et al. Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis. J Ethnopharmacol. 2021;281:114571.PubMedCrossRef Song C, Yang C, Meng S, et al. Deciphering the mechanism of Fang-Ji-Di-Huang-Decoction in ameliorating psoriasis-like skin inflammation via the inhibition of IL-23/Th17 cell axis. J Ethnopharmacol. 2021;281:114571.PubMedCrossRef
5.
Zurück zum Zitat Fu S, Cheng R, Deng Z, Liu T. Qualitative analysis of chemical components in Lianhua Qingwen capsule by HPLC-Q Exactive-Orbitrap-MS coupled with GC-MS. J Pharm Anal. 2021;11(6):709–16.PubMedPubMedCentralCrossRef Fu S, Cheng R, Deng Z, Liu T. Qualitative analysis of chemical components in Lianhua Qingwen capsule by HPLC-Q Exactive-Orbitrap-MS coupled with GC-MS. J Pharm Anal. 2021;11(6):709–16.PubMedPubMedCentralCrossRef
6.
Zurück zum Zitat Hone SW, Donnelly MJ, Powell F, Blayney AW. Clearance of recalcitrant psoriasis after tonsillectomy. Clin Otolaryngol. 1996;21(6):546–7.PubMedCrossRef Hone SW, Donnelly MJ, Powell F, Blayney AW. Clearance of recalcitrant psoriasis after tonsillectomy. Clin Otolaryngol. 1996;21(6):546–7.PubMedCrossRef
7.
Zurück zum Zitat McMillin BD, Maddern BR, Graham WR. A role for tonsillectomy in the treatment of psoriasis? Ear Nose Throat J. 1999;78(3):155–8.PubMedCrossRef McMillin BD, Maddern BR, Graham WR. A role for tonsillectomy in the treatment of psoriasis? Ear Nose Throat J. 1999;78(3):155–8.PubMedCrossRef
8.
Zurück zum Zitat Diluvio L, Vollmer S, Besgen P, Ellwart JW, Chimenti S, Prinz JC. Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris. J Immunol. 2006;176(11):7104–11.PubMedCrossRef Diluvio L, Vollmer S, Besgen P, Ellwart JW, Chimenti S, Prinz JC. Identical TCR beta-chain rearrangements in streptococcal angina and skin lesions of patients with psoriasis vulgaris. J Immunol. 2006;176(11):7104–11.PubMedCrossRef
9.
Zurück zum Zitat Brand N, Petkovich M, Krust A, et al. Identification of a second human retinoic acid receptor. Nature. 1988;332(6167):850–3.PubMedCrossRefADS Brand N, Petkovich M, Krust A, et al. Identification of a second human retinoic acid receptor. Nature. 1988;332(6167):850–3.PubMedCrossRefADS
10.
Zurück zum Zitat Harper RA. Specificity in the synergism between retinoic acid and egf on the growth of adult human-skin fibroblasts. Exp Cell Res. 1988;178(2):254–63.PubMedCrossRefADS Harper RA. Specificity in the synergism between retinoic acid and egf on the growth of adult human-skin fibroblasts. Exp Cell Res. 1988;178(2):254–63.PubMedCrossRefADS
11.
Zurück zum Zitat Gniadecki R, Bang B, Bryld LE, Iversen L, Lasthein S, Skov L. Comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris. Br J Dermatol. 2015;172(1):244–52.PubMedCrossRef Gniadecki R, Bang B, Bryld LE, Iversen L, Lasthein S, Skov L. Comparison of long-term drug survival and safety of biologic agents in patients with psoriasis vulgaris. Br J Dermatol. 2015;172(1):244–52.PubMedCrossRef
12.
Zurück zum Zitat Li TT, Pan J, Chen HQ, Fang YL, Sun Y. CXCR6-based immunotherapy in autoimmune, cancer and inflammatory infliction. Acta Pharmaceutica Sinica B. 2022;12(8):3255–62.PubMedPubMedCentralCrossRef Li TT, Pan J, Chen HQ, Fang YL, Sun Y. CXCR6-based immunotherapy in autoimmune, cancer and inflammatory infliction. Acta Pharmaceutica Sinica B. 2022;12(8):3255–62.PubMedPubMedCentralCrossRef
13.
Zurück zum Zitat Lee HS, Kwon SH, Lee ES. Comparative study of clinical characteristics according to therapeutic efficacy and drug survival of cyclosporine or methotrexate in psoriasis vulgaris. Ann Dermatol. 2019;31(4):469–72.PubMedPubMedCentralCrossRef Lee HS, Kwon SH, Lee ES. Comparative study of clinical characteristics according to therapeutic efficacy and drug survival of cyclosporine or methotrexate in psoriasis vulgaris. Ann Dermatol. 2019;31(4):469–72.PubMedPubMedCentralCrossRef
14.
Zurück zum Zitat Thayer S, Watson C, Song R, Globe DR, Harrison DJ. Etanercept treatment patterns in managed-care patients with psoriasis or psoriatic arthritis. J Med Econ. 2010;13(2):228–35.PubMedCrossRef Thayer S, Watson C, Song R, Globe DR, Harrison DJ. Etanercept treatment patterns in managed-care patients with psoriasis or psoriatic arthritis. J Med Econ. 2010;13(2):228–35.PubMedCrossRef
15.
Zurück zum Zitat Young HS, Summers AM, Read IR, et al. Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis. J Invest Dermatol. 2006;126(2):453–9.PubMedCrossRef Young HS, Summers AM, Read IR, et al. Interaction between genetic control of vascular endothelial growth factor production and retinoid responsiveness in psoriasis. J Invest Dermatol. 2006;126(2):453–9.PubMedCrossRef
16.
Zurück zum Zitat Halin C, Fahrngruber H, Meingassner JG, et al. Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Am J Pathol. 2008;173(1):265–77.PubMedPubMedCentralCrossRef Halin C, Fahrngruber H, Meingassner JG, et al. Inhibition of chronic and acute skin inflammation by treatment with a vascular endothelial growth factor receptor tyrosine kinase inhibitor. Am J Pathol. 2008;173(1):265–77.PubMedPubMedCentralCrossRef
17.
Zurück zum Zitat Schon MP, Zollner TM, Boehncke WH. The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J Invest Dermatol. 2003;121(5):951–62.PubMedCrossRef Schon MP, Zollner TM, Boehncke WH. The molecular basis of lymphocyte recruitment to the skin: clues for pathogenesis and selective therapies of inflammatory disorders. J Invest Dermatol. 2003;121(5):951–62.PubMedCrossRef
18.
Zurück zum Zitat Han MR, Li CX, Zhang CY, et al. Single-cell transcriptomics reveals the natural product Shi-Bi-Man promotes hair regeneration by activating the FGF pathway in dermal papilla cells. Phytomedicine. 2022;104:154260.PubMedCrossRef Han MR, Li CX, Zhang CY, et al. Single-cell transcriptomics reveals the natural product Shi-Bi-Man promotes hair regeneration by activating the FGF pathway in dermal papilla cells. Phytomedicine. 2022;104:154260.PubMedCrossRef
19.
Zurück zum Zitat Cai L, Chen GH, Lu QJ, et al. A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis. Chin Med J (Engl). 2020;133(24):2905–9.PubMedCrossRef Cai L, Chen GH, Lu QJ, et al. A double-blind, randomized, placebo- and positive-controlled phase III trial of 1% benvitimod cream in mild-to-moderate plaque psoriasis. Chin Med J (Engl). 2020;133(24):2905–9.PubMedCrossRef
20.
Zurück zum Zitat Luengas-Martinez A, Paus R, Young HS. Antivascular endothelial growth factor-A therapy: a novel personalized treatment approach for psoriasis. Brit J Dermatol. 2022;186(5):782–91.CrossRef Luengas-Martinez A, Paus R, Young HS. Antivascular endothelial growth factor-A therapy: a novel personalized treatment approach for psoriasis. Brit J Dermatol. 2022;186(5):782–91.CrossRef
21.
22.
Zurück zum Zitat Raychaudhuri SK, Saxena A, Raychaudhuri SP. Role of IL-17 in the pathogenesis of psoriatic arthritis and axial spondyloarthritis. Clin Rheumatol. 2015;34(6):1019–23.PubMedCrossRef Raychaudhuri SK, Saxena A, Raychaudhuri SP. Role of IL-17 in the pathogenesis of psoriatic arthritis and axial spondyloarthritis. Clin Rheumatol. 2015;34(6):1019–23.PubMedCrossRef
24.
Zurück zum Zitat Wang M, Li T, Ouyang Z, et al. SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis. iScience. 2022;25(4):104009.PubMedPubMedCentralCrossRefADS Wang M, Li T, Ouyang Z, et al. SHP2 allosteric inhibitor TK-453 alleviates psoriasis-like skin inflammation in mice via inhibition of IL-23/Th17 axis. iScience. 2022;25(4):104009.PubMedPubMedCentralCrossRefADS
25.
Zurück zum Zitat Garshick MS, Barrett TJ, Wechter T, et al. Inflammasome signaling and impaired vascular health in psoriasis. Arterioscler Thromb Vasc Biol. 2019;39(4):787–98.PubMedPubMedCentralCrossRef Garshick MS, Barrett TJ, Wechter T, et al. Inflammasome signaling and impaired vascular health in psoriasis. Arterioscler Thromb Vasc Biol. 2019;39(4):787–98.PubMedPubMedCentralCrossRef
26.
Zurück zum Zitat Hugh JM, Weinberg JM. Update on the pathophysiology of psoriasis. Cutis. 2018;102(5S):6–12.PubMed Hugh JM, Weinberg JM. Update on the pathophysiology of psoriasis. Cutis. 2018;102(5S):6–12.PubMed
27.
Zurück zum Zitat Luengas-Martinez A, Hardman-Smart J, Paus R, Young HS. Vascular endothelial growth factor-A as a promising therapeutic target for the management of psoriasis. Exp Dermatol. 2020;29(8):687–98.PubMedCrossRef Luengas-Martinez A, Hardman-Smart J, Paus R, Young HS. Vascular endothelial growth factor-A as a promising therapeutic target for the management of psoriasis. Exp Dermatol. 2020;29(8):687–98.PubMedCrossRef
28.
Zurück zum Zitat Zhao Q, Yu J, Zhou H, et al. Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism. Signal Transduct Target Ther. 2023;8(1):40.PubMedPubMedCentralCrossRef Zhao Q, Yu J, Zhou H, et al. Intestinal dysbiosis exacerbates the pathogenesis of psoriasis-like phenotype through changes in fatty acid metabolism. Signal Transduct Target Ther. 2023;8(1):40.PubMedPubMedCentralCrossRef
29.
Zurück zum Zitat Lei L, Yan B, Liu P, et al. Lysophosphatidic acid mediates the pathogenesis of psoriasis by activating keratinocytes through LPAR5. Signal Transduct Target Ther. 2021;6(1):19.PubMedPubMedCentralCrossRef Lei L, Yan B, Liu P, et al. Lysophosphatidic acid mediates the pathogenesis of psoriasis by activating keratinocytes through LPAR5. Signal Transduct Target Ther. 2021;6(1):19.PubMedPubMedCentralCrossRef
30.
Zurück zum Zitat Ding Y, Ouyang Z, Zhang C, et al. Tyrosine phosphatase SHP2 exacerbates psoriasis-like skin inflammation in mice via ERK5-dependent NETosis. MedComm. 2022;3(1):e120.PubMedPubMedCentralCrossRef Ding Y, Ouyang Z, Zhang C, et al. Tyrosine phosphatase SHP2 exacerbates psoriasis-like skin inflammation in mice via ERK5-dependent NETosis. MedComm. 2022;3(1):e120.PubMedPubMedCentralCrossRef
31.
Zurück zum Zitat Zhu Y, Wu Z, Yan W, et al. Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis. EMBO Mol Med. 2022;14(3):e14455.PubMedCrossRef Zhu Y, Wu Z, Yan W, et al. Allosteric inhibition of SHP2 uncovers aberrant TLR7 trafficking in aggravating psoriasis. EMBO Mol Med. 2022;14(3):e14455.PubMedCrossRef
32.
Zurück zum Zitat Zhu YY, Ouyang ZJ, Du HJ, et al. New opportunities and challenges of natural products research: When target identification meets single-cell multiomics. Acta Pharmaceutica Sinica B. 2022;12(11):4011–39.PubMedPubMedCentralCrossRef Zhu YY, Ouyang ZJ, Du HJ, et al. New opportunities and challenges of natural products research: When target identification meets single-cell multiomics. Acta Pharmaceutica Sinica B. 2022;12(11):4011–39.PubMedPubMedCentralCrossRef
33.
Zurück zum Zitat Zhu Y, Ouyang Z, Du H, et al. New opportunities and challenges of natural products research: When target identification meets single-cell multiomics. Acta Pharm Sin B. 2022;12(11):4011–39.PubMedPubMedCentralCrossRef Zhu Y, Ouyang Z, Du H, et al. New opportunities and challenges of natural products research: When target identification meets single-cell multiomics. Acta Pharm Sin B. 2022;12(11):4011–39.PubMedPubMedCentralCrossRef
34.
Zurück zum Zitat Chen XM, Liu YH, Ji SF, et al. Protective effect of ginsenoside Rd on military aviation noise-induced cochlear hair cell damage in guinea pigs. Environ Sci Pollut Res Int. 2023;30(9):23965–81.PubMedCrossRef Chen XM, Liu YH, Ji SF, et al. Protective effect of ginsenoside Rd on military aviation noise-induced cochlear hair cell damage in guinea pigs. Environ Sci Pollut Res Int. 2023;30(9):23965–81.PubMedCrossRef
35.
Zurück zum Zitat Yang C, Song C, Wang Y, et al. Re-Du-Ning injection ameliorates radiation-induced pneumonitis and fibrosis by inhibiting AIM2 inflammasome and epithelial-mesenchymal transition. Phytomedicine. 2022;102:154184.PubMedCrossRef Yang C, Song C, Wang Y, et al. Re-Du-Ning injection ameliorates radiation-induced pneumonitis and fibrosis by inhibiting AIM2 inflammasome and epithelial-mesenchymal transition. Phytomedicine. 2022;102:154184.PubMedCrossRef
36.
Zurück zum Zitat Yang C, Song C, Liu Y, et al. Re-Du-Ning injection ameliorates LPS-induced lung injury through inhibiting neutrophil extracellular traps formation. Phytomedicine. 2021;90:153635.PubMedPubMedCentralCrossRef Yang C, Song C, Liu Y, et al. Re-Du-Ning injection ameliorates LPS-induced lung injury through inhibiting neutrophil extracellular traps formation. Phytomedicine. 2021;90:153635.PubMedPubMedCentralCrossRef
37.
Zurück zum Zitat Tan SJ, Yu Z, Dong QT. Effects of ginsenoside Rb1 on the oxidative stress in the skeletal muscles of rats with postoperative fatigue syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012;32(11):1535–8.PubMed Tan SJ, Yu Z, Dong QT. Effects of ginsenoside Rb1 on the oxidative stress in the skeletal muscles of rats with postoperative fatigue syndrome. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2012;32(11):1535–8.PubMed
38.
Zurück zum Zitat Liu S, Cao X, Zhang T, et al. Paeonol ameliorates endometrial hyperplasia in mice via inhibiting PI3K/AKT pathway-related ferroptosis. Phytomedicine. 2023;109:154593.PubMedCrossRef Liu S, Cao X, Zhang T, et al. Paeonol ameliorates endometrial hyperplasia in mice via inhibiting PI3K/AKT pathway-related ferroptosis. Phytomedicine. 2023;109:154593.PubMedCrossRef
39.
Zurück zum Zitat Nguyen LTH, Ahn SH, Nguyen UT, Yang IJ. Dang-Gui-Liu-Huang Tang a traditional herbal formula, ameliorates imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-22 production. Phytomedicine. 2018;47:48–57.PubMedCrossRef Nguyen LTH, Ahn SH, Nguyen UT, Yang IJ. Dang-Gui-Liu-Huang Tang a traditional herbal formula, ameliorates imiquimod-induced psoriasis-like skin inflammation in mice by inhibiting IL-22 production. Phytomedicine. 2018;47:48–57.PubMedCrossRef
40.
Zurück zum Zitat Deng G, Chen W, Wang P, et al. Inhibition of NLRP3 inflammasome-mediated pyroptosis in macrophage by cycloastragenol contributes to amelioration of imiquimod-induced psoriasis-like skin inflammation in mice. Int Immunopharmacol. 2019;74:105682.PubMedCrossRef Deng G, Chen W, Wang P, et al. Inhibition of NLRP3 inflammasome-mediated pyroptosis in macrophage by cycloastragenol contributes to amelioration of imiquimod-induced psoriasis-like skin inflammation in mice. Int Immunopharmacol. 2019;74:105682.PubMedCrossRef
41.
Zurück zum Zitat Lin P, Lu JM, Wang YF, Gu W, Yu J, Zhao RH. Naturally occurring stilbenoid TSG reverses non-alcoholic fatty liver diseases via gut-liver axis. plos one. 2015;10(10):e0140346.PubMedPubMedCentralCrossRef Lin P, Lu JM, Wang YF, Gu W, Yu J, Zhao RH. Naturally occurring stilbenoid TSG reverses non-alcoholic fatty liver diseases via gut-liver axis. plos one. 2015;10(10):e0140346.PubMedPubMedCentralCrossRef
42.
Zurück zum Zitat Zhang L, Yu S, Zhang RY, Xing Y, Li YH, Li L. Tetrahydroxystilbene glucoside antagonizes age-related alpha-synuclein overexpression in the hippocampus of APP transgenic mouse model of Alzheimer’s disease. Restor Neurol Neuros. 2013;31(1):41–52. Zhang L, Yu S, Zhang RY, Xing Y, Li YH, Li L. Tetrahydroxystilbene glucoside antagonizes age-related alpha-synuclein overexpression in the hippocampus of APP transgenic mouse model of Alzheimer’s disease. Restor Neurol Neuros. 2013;31(1):41–52.
44.
Zurück zum Zitat Garshick MS, Ward NL, Krueger JG, Berger JS. Cardiovascular risk in patients with psoriasis: JACC review topic of the week. J Am Coll Cardiol. 2021;77(13):1670–80.PubMedPubMedCentralCrossRef Garshick MS, Ward NL, Krueger JG, Berger JS. Cardiovascular risk in patients with psoriasis: JACC review topic of the week. J Am Coll Cardiol. 2021;77(13):1670–80.PubMedPubMedCentralCrossRef
Metadaten
Titel
Traditional Chinese Medicine Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation
verfasst von
Chenyang Zhang
Xinran Cao
Lixin Zhao
Zitong Ni
Haojie Du
Jiao Qu
Jianxia Zhu
Haiyan Sun
Yang Sun
Zijun Ouyang
Publikationsdatum
01.12.2024
Verlag
BioMed Central
Erschienen in
Chinese Medicine / Ausgabe 1/2024
Elektronische ISSN: 1749-8546
DOI
https://doi.org/10.1186/s13020-024-00907-z

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