Heparanase contributes to psoriatic lesions through crosstalk with IL-17 pathway

   Abstract 


Psoriasis is a chronic inflammatory disease that is considered by a network of immunocytes and cytokines. Among all, Th17 cells–derived IL-17 is a critical driving factor in the pathogenesis of psoriasis. Recently, disruption of the extracellular matrix was found to be related to psoriasis progression. In the present study, we aimed to investigate the role of heparanase (HPSE) in psoriasis and the crosstalk with the IL-17 signalling pathway. Skin tissues from non-affected areas and psoriatic lesion areas before and after 12 weeks of IL-17 monoclonal antibody treatment of 30 psoriasis patients were collected. HaCaT cells were treated with different concentrations of IL-17 antibody, and HPSE in cells and medium were measured with Western blotting assay as well as enzyme-linked immunosorbent assay (ELISA). In the imiquimod (IMQ)-induced psoriasis model, IL-17 protein and mRNA expression levels were measured, and changes in the proportion of Th17 cells were detected via flow cytometry. Our data showed that HPSE is upregulated in lesion tissues isolated from psoriasis patients, and was inhibited by anti-IL-17 treatment. In cutaneous cells and IMQ-induced psoriasis model, IL-17 promoted the synthesis of HPSE. Inversely, HPSE was also found to increase the percentage of Th17 cells derived from CD4+ T cells. Finally, we found that the combined treatments of HPSE inhibitor and IL-17 monoclonal antibody produced therapeutic effects on IMQ-induced psoriasis model. Our findings revealed the new role of HPSE in the pathogenesis of psoriasis and also provided a target for combined treatment of psoriasis.

Keywords: Heparanase, IL-17, psoriasis, Th17 cells


How to cite this article:
Zhu C, Ren Y, Yao H, Feng B, Liu L, Zheng M. Heparanase contributes to psoriatic lesions through crosstalk with IL-17 pathway. Indian J Dermatol 2023;68:59-66
How to cite this URL:
Zhu C, Ren Y, Yao H, Feng B, Liu L, Zheng M. Heparanase contributes to psoriatic lesions through crosstalk with IL-17 pathway. Indian J Dermatol [serial online] 2023 [cited 2023 Apr 1];68:59-66. Available from: 
https://www.e-ijd.org/text.asp?2023/68/1/59/373050    Introduction Top

Psoriasis is a chronic skin disease characterized by inflammation and a series of skin alterations, including epidermal hyperplasia, increased dermal angiogenesis as well as dense infiltrates of immunocytes.[1] Currently, the main pathogenesis process of psoriasis is considered as the coordination of innate immunity and adaptive immune response.[2],[3] For instance, it has been reported that immunocytes including macrophages, dendritic cells, as well as T cells are closely related to psoriasis.[4],[5] Cytokines such as interleukin (IL)-17 and IL-23, secreted from these inflammatory cells also contribute to the progression of psoriasis.[1] Targeting IL-17 is also currently used as the main strategy for the therapy of psoriasis.[1] Due to the high incidence of psoriasis and severe complications,[1] it is urgently required to identify novel target and the mechanism of psoriasis.

Recently, the essential roles of extracellular matrix such as proteoglycans and metalloproteinases have been demonstrated to contribute to the progression of psoriasis.[6],[7] CD138 is a member of heparan sulphate proteoglycans, composed of the core proteins and heparan sulphate, which was specially degraded by the heparanase (HPSE) enzyme.[8] Notably, HPSE is the sole mammalian endoglycosidase which degrades heparan sulphate, the key polysaccharide associated with the cell surface and extracellular matrix of many tissues.[9] Recently, it was reported that is possibly related to cutaneous inflammations, including activation of NF-κB, triggering the secretion of cytokines including IL-1β, IL-6, IL-8, and IL-10, as well as TNF-α.[10] HPSE is also shown to contribute to gastritis, liver steatosis,[11] and coronavirus disease 2019 (COVID-19).[12] Strikingly, HPSE was also found to be upregulated in psoriasis and plays a possible role in its pathogenesis.[10] However, the role of HPSE and the detailed mechanism in psoriasis are unclear.

In the present study, we aimed to investigate the role of HPSE in the pathogenesis of psoriasis and the regulatory role of HPSE-IL-17 crosstalk. We first analysed the expression of HPSE in psoriasis patients before and after 12 weeks of IL-17 antibody treatment and then determined the effect of IL-17 on HPSE expressions in vitro and in vivo. Through HPSE inhibitor treatment, we further detected the percentage of Th17 and IL-17 secretion. Combined treatments with HPSE inhibitor and IL-17 antibody reduced cutaneous inflammation. Together, our work provides a novel mechanism and strategy for the treatment of psoriasis.

   Materials and Methods Top

Patient samples and IHC analysis

Skin tissues from non-affected areas and areas of psoriatic lesion before and after 12 weeks of IL-17 monoclonal antibody treatment of 30 psoriasis patients were collected from the department of dermatology, The Fourth Affiliated Hospital of Zhejiang University School of Medicine. The patients were subcutaneously injected with 160 mg Ixekizumab, then 80mg every 2 weeks at weeks 2-12. All the procedures of the experiment were approved by the ethics committee of the Fourth Affiliated Hospital of Zhejiang University. The tissues were then subjected to immunohistochemistry staining for HPSE and IL-17 with specific antibodies. Briefly, paraffin-fixed slides were cut into 3-nm slides and incubated in 3% H2O2, then antigen unmasking was conducted by heating for 20 min in 10 mm Tris buffer supplemented with Ethylenediaminetetraacetic acid (EDTA). Slides were incubated with primary antibodies for HPSE or IL-17 diluted in 1% goat serum buffer, after which the slides were incubated in relative secondary antibody. Colour was developed using the the DAB substrate kit (Beyotime, Haimen, China) followed by counterstaining with haematoxylin and eosin (H and E) staining. Images were taken with a light microscope and the positive rate per field was analysed by using ImageJ software.

Cells and treatments

Human skin HaCaT cells were purchased from the American Type Culture Collection (ATCC, USA) and maintained in DMEM medium supplemented with 10% foetal bovine serum (FBS) in a humified incubator at 37°C. Before further experiments, the cells were expanded in 10-cm dishes and then plated into 6-well plates at a concentration of 2 × 105 per well. At 24 h after the cell seeded, the cells were treated with different concentrations of IL-17 antibody. Then the cells were collected and HPSE in cells and medium were measured with Western blotting assay as well as enzyme-linked immunosorbent assay (ELISA).

Realtime PCR assay

Total RNA was extracted from HaCaT cells, and mice skin was isolated from different groups by using a TRIzol reagent (Invitrogen, USA) according to the manufacturer's instructions. Then complementary DNAs (cDNAs) were reverse-transcribed by using a cDNA synthesis kit (Takara, Dalian, China) using the manufacturer's instructions. The real-time polymerase chain reaction (PCR) assay was performed with a SYBR Real-time PCR kit (Takara, Dalian, China) on an ABI7200 machine. The primers used for real-time PCR analysis were listed as follows: murine, IL-17, forward, 5′-CTCAAAGCTCAGCGTGTCCAA-3′, reverse, 5′-TCATGTGGTGGTCCAGCTTTC-3′. murine HPSE, forward, 5′-ACTTGAAGGTACCGCCTCCG-3′, reverse, 5′-GAAGCTCTGGAACTCGGCAA-3′. GAPDH was used as a negative control, forward, 5′-ACCACAGTCCATGCCATCAC-3′, reverse, 5′-TCCACCACCCTGTTGCTGTA-3′.[10],[13]

Western blotting assay

For detection of HPSE in cells and skin tissues, protein was extracted with a RIPA lysis buffer (Thermo scientific, USA). Then the proteins were subjected to SDS-PAGE for the separation of different proteins. The proteins in SDS-PAGE were then transferred to a NC membrane (Beyotime, China) according to the manufacturer's instructions. Then membranes were blocked with 5% milk and incubated with primary antibodies overnight at 4°C as follows: HPSE (CST, 1:1000), IL-17 (CST, 1:1000), GAPDH (Proteintech, 1:1000). The membrane was then incubated with secondary antibodies at room temperature for 1 h. The images were taken with a Chemiluminescence detector after being incubated with an enhanced chemiluminescence (ECL) kit (Syngene, USA).

ELISA assay

The concentration of HPSE and IL-17 in mouse tissues and the cell medium were measured with an ELISA kit according to the manufacturer's instructions (CUSABIO Co., Westang Co.). After incubating with the detecting system, the 96-well plates were detected at OD570 in a plate reader (BioTech., USA).

Flow cytometry analysis

Flow cytometry analysis was used to detect the differentiation of T cells as previously described.[14],[15] Briefly, T cells were isolated from human peripheral blood with depleting red blood cells and selected with CD3-specific microbead in Model-based Analysis of ChIP-Seq (MACS). The sorted cells were then plated into 6-well plates and treated with recombinant HPSE for 36–72 h. Flow cytometry analysis was used to measure the percentages of Th17 cells with the combined markers of IL-17-PE and CD4-FITC antibodies (Ebioscience, USA). The percentages of different cells were quantitatively analysed and statistical analysis was also performed.

Mice model of psoriasis and treatment

All of our experimental procedures and protocols were well approved by Zhejiang University of China in accordance with the Guide for Care and Use of Laboratory Animals published by the US National Institutes of Health (NIH) (publication No. 96-01). Balb/c mice of wild type (6–8 weeks old, China Academy of Science, Shanghai, China) were selected for the animal experiments. To establish the mice model of psoriasis, mice were topically administered with imiquimod cream (IMQ, 3M, USA) on the back skin, which was used as a common psoriasis mice model.[16],[17] Briefly, IMQ cream of 5% was evenly applied to the alopecia area at a dose of 50 mg/cm2, once a day for 6 days. After the model was established, the mice were intraperitoneally injected with IgG control (Proteintech Co.), IL-17 antibody (Proteintech Co.), and IL-17+ HPSE inhibitor (OGT 2115). Seven and 10 days after treatments, the IMQ-treated area of the skin was isolated and subjected to immunohistochemistry (IHC) staining, ELISA, and RT-PCR analysis of HPSE and IL-17.

Statistical analysis

All the data were expressed as mean standard error of the mean (SEM). For comparison among different groups, the analysis was performed using a one-way analysis of variance (ANOVA). For comparison between two groups, student's t-test was conducted and P < 0.05 was considered as statistically significant. The values were calculated and analysed with a GraphPad Prism 8 software. All the experiments were repeated three independent times.

   Results Top

1 Clinical relevance of HPSE and IL-17A in clinical psoriasis patients

Skin tissues of the non-affected area and the psoriatic lesion area before and after 12 weeks of IL-17 monoclonal antibody treatment of 30 psoriasis patients were collected [Table 1] and [Table 2]. After tissue sectioning, HPSE and CD138 IHC staining and Pearson correlation analysis were carried out, and the expression levels of HPSE and CD138 in the skin tissues of patients with psoriasis were significantly higher than those in the control group [Figure 1]a and [Figure 1]b. However, in the IL-17A monoclonal antibody treatment group, the expression levels of HPSE and CD138 were significantly reduced, indicating that the high expression of HPSE may be related to the development of psoriasis [Figure 1]a and [Figure 1]c. Moreover, IL-17 monoclonal antibody therapy can effectively inhibit HPSE expression.

Figure 1: Clinical relevance of HPSE and IL-17A in clinical psoriasis patients. (a) IHC staining of HPSE and CD138 in non-affected area, psoriatic lesion's area before and after 12 weeks IL-17 antibody treatment. (b and c) Quantification of HPSE and CD138 expression density in different groups. *P < 0.05 vs psoriasis group. **P < 0.01 vs psoriasis groups

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2 IL-17 promotes the secretion of HPSE in human HaCaT cells

Human skin HaCaT cells were treated with recombinant human IL-17, and then the expression and secretion levels of HPSE were detected using RT-PCR and ELISA. It was found that after IL-17 treatment, the mRNA expression level and protein level of HPSE were significantly upregulated [Figure 2]a and [Figure 2]b, indicating that IL-17 had a promoting effect on the expression of HPSE in cultured cells.

Figure 2: IL-17 promotes the secretion of HPSE in human HaCaT cells. (a) Relative expression of HPSE mRNA was measured through RT-PCR assay in IL-17-treated HaCaT cells. (b) Protein expression of HPSE was measured by Western blotting assay in HaCaT cells at 12 and 24 h after IL-17 treatment. *P < 0.05 vs control group. **P < 0.01 vs control groups

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3 IL-17 monoclonal antibody reduces the level of HPSE in mice model of psoriasis

IMQ-induced psoriasis model is widely used in the study of psoriasis and therapeutic strategies. In the present study, we established mice psoriasis model through spreading IMQ cream of 5% on the alopecia area at a dose of 50 mg/cm2 once a day for 6 days. In mice of the IL-17 antibody–treated psoriasis model, we also found that the expression of HPSE decreased significantly in their skin tissues of those given IL-17A monoclonal antibody [Figure 3]a, [Figure 3]b, [Figure 3]c. These data were consistent with the data on human HaCaT cells, showing that IL-17 promoted the synthesis of HPSE in vitro and in vivo.

Figure 3: IL-17 monoclonal antibody reduced the level of HPSE in mice model of psoriasis. (a) Representative images of IHC staining of HPSE in IL-17-treated mice psoriasis model. (b and c) mRNA expression and protein expression of IL-17 in skin tissues in IMQ-induced psoriasis model. *P < 0.05 vs psoriasis group

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4 HPSE promotes Th17 differentiation in T cells isolated from human peripheral blood

We isolated human peripheral blood T cells and then treated with HPSE; after different times of treatment, the proportion of CD4+ T cells differentiated into Th17 cells was detected. Our data showed that after HPSE treatment, the proportion of Th17 cells increased significantly [Figure 4]a and [Figure 4]b, and ELISA assay results showed an increase in IL-17 secretion [Figure 4c], indicating that HPSE promoted the differentiation of Th17 cells.

Figure 4: HPSE promotes Th17 differentiation in T cells isolated from human peripheral blood. (a) Representative images of flow cytometry analysis of Th17 cells in CD4+ T cell derived model. (b) Quantitative analysis of IL-17A positive cells after different treatments. (c) Concentration of IL-17 was measured with ELISA. *P < 0.05 vs control group. **P < 0.01 vs control groups

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5 HPSE inhibitor reduces the percentage of Th17 cells and the level IL-17 in vivo

In the animal model of psoriasis, we intraperitoneally injected HPSE inhibitor at a dose of 20 mg/kg, and then detected changes in IL-17 protein and mRNA expression levels and changes in the proportion of Th17 cells by flow cytometry. Both ELISA results and RT-PCR results also revealed that IL-17 levels also decreased significantly [Figure 5]a and [Figure 5]b, and the proportion of Th17 cells was also significantly reduced [Figure 5]c and [Figure 5]d, indicating that skin keratinocyte-derived HPSE and Th17 cell–derived IL-17 were mutually reinforcing.

Figure 5: HPSE inhibitor reduced the percentage of Th17 cells and the level of IL-17 in vivo. (a and b) mRNA expression and protein concentration of IL-17 was measured by RT-PCR assay and ELISA in psoriasis tissues. (c-d) Representative images of flow cytometry for Th17 cells and the quantifications. *P < 0.05 vs psoriasis group. **P < 0.01 vs psoriasis groups

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6 HPSE inhibitor combined with IL-17A antibody showed better effects on psoriasis in vivo

Finally, we treated psoriasis mice with both IL-17 monoclonal antibody and HPSE inhibitors after the establishment of psoriasis model of imiquimod cream. No significant changes in the body weight of mice with psoriasis were found [Figure 6]a. However, the skin tissue had significantly thinned and the infiltration of inflammatory cells had weakened [Figure 6]b and [Figure 6]c, indicating that the treatment effect of psoriasis was better than that of the drug group alone, in turn indicating that the combination of drugs achieved better results.

Figure 6: HPSE inhibitor combined with IL-17A antibody showed better effects on psoriasis in vivo. (a) Representative images of H and E staining of skin tissues of psoriasis mice treated with combined IL-17 antibody and HPSE inhibitors. (b and c) Bodyweight and skin thickness of psoriasis mice treated with different models were measured at day 1 to day 5. *P < 0.05 vs psoriasis group. **P < 0.01 vs psoriasis groups

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   Discussion Top

In this study, we investigated the regulatory relationship between HPSE and IL-17 in cells and mice models. First, the expression levels of HPSE and CD138 in the skin tissues of patients with psoriasis were observed to be significantly higher than those in the control group, whereas it was reduced in the IL-17A monoclonal antibody treatment group. IL-17 treatment increased the mRNA expression level and protein level of HPSE. Further experiments showed that HPSE promoted Th17 cells differentiation and IL-17 production. Finally, combined treatment of both IL-17 monoclonal antibody and HPSE inhibitor showed better therapeutic effects on IMQ-induced psoriasis model, providing novel strategies.

Psoriasis is a chronic inflammation and cutaneous disease characterized by infiltration of immunocytes including macrophage, dendritic cells, as well as Th17 cells, accompanied by upregulation of cytokines such as IL-17 and IL-23.[18],[19] Recently, the role of the extracellular matrix (ECM) in psoriasis is drawing more and more attention.[20] Among all, matrix metalloproteinases (MMPs) participated in the disruption of ECM, contributing to the pathogenesis of psoriasis.[21],[22] CD138 was also observed to be elevated in skin tissues in psoriasis patients.[23] As a key member of heparan sulphate proteoglycans, CD138 is composed of the core proteins and heparan sulphate, which was specially degraded by HPSE.[8],[24] Recently, the role of HPSE in psoriasis was also investigated, and some groups found that HPSE was related to the progression of psoriasis.[10],[25] HPSE was also reported to be related to the function of MMP9 in psoriasis.[26] Consistently, our data from clinical patients also revealed that HPSE was significantly upregulated in psoriasis patients. Additionally, our study showed that HPSE was related to IL-17 antibody treatment—a widely used treatment strategy for psoriasis patients.[2] Our observation suggests a strong link between the upregulation of HPSE and IL-17 signalling pathway.

The role of IL-17 in psoriasis was well established and monoclonal antibody was also developed for clinical applications.[27],[28] To investigate the crosstalk of HPSE and IL-17 production, we first studied the influence of IL-17 on HPSE expression. Our data showed that recombinant IL-17 significantly induced the synthesis of HPSE, indicating that IL-17 and its downstream pathways may involve in the regulation of HPSE. However, in our study of HPSE on the differentiation of IL-17, we surprisingly observed the increase of Th17 cell percentages. These data showed that HPSE may inversely stimulate the differentiation of Th17 cells. Consequently, the mRNA level as well as protein level of IL-17 was downregulated by HPSE inhibitor treatment. These findings provide a novel mechanism for the regulatory network of psoriasis, which may provide a novel opportunity for clinical therapy.

Next, we established an IMQ-induced psoriasis model, as previously described, and investigated the possible therapeutic effects of combination of IL-17 and HPSE inhibitor.[17] Then we detected the skin thickness and inflammation immunocytes and observed effective therapeutic advantages. Nowadays, psoriasis is often treated with IL-17 antibody, Chinese herbs, anti-inflammation treatments, as well as vitamin D etc.[29],[30],[31],[32] Among all the therapeutic strategies, anti-IL-17 therapy, including secukinumab, ixekizumab, and brodalumab represent the main treatment strategy clinically used for patients.[33] Our findings of the combined treatment provide a better method for treating psoriasis, which may also benefit from the development of novel low-toxic HPSE inhibitors.

Our study provided novel mechanism and possible strategy for the treatment of psoriasis; however, there are also shortcomings that need to be figured out in further studies. First, the extensive role of HPSE in psoriasis needs to be addressed in different cells and animal models. Second, the regulatory role of HPSE on Th17 cell differentiation needs to be investigated in detail. Whether the underlying signalling pathway may be influenced by HPSE was unclear. Finally, the treatment strategy of combination of IL-17 and HPSE should be tested and compared with current treatment strategies, Then the novel combination treatment strategy can be accepted by the patients and applied clinically.

In conclusion, we demonstrated that HPSE was upregulated in psoriasis patients and investigated its crosstalk with IL-17 signalling pathway. We observed that IL-17 promoted the production of HPSE, which inversely stimulated the differentiation of Th17 cells to form a positive feedback loop. The combination of anti-IL-17 and HPSE inhibitor showed high efficacy in treating psoriasis in the mice model. Finally, our finding provides a novel mechanism of HPSE and novel target for psoriasis treatment.

Availability of data and materials

The datasets used and analysed during the current study are available within the manuscript and its additional files.

Ethics approval and consent to participate

The whole study design and protocols were approved by the Ethics Committee of Zhejiang University, China, in accordance with the instruction about Care and Use of Laboratory Animals published by the US NIH (Publication No. 96-01).

Consent for publication

All authors have agreed to publish this manuscript.

Financial support and sponsorship

This study was supported in part by the grants from National Natural Science Foundation of China (81872520), Zhejiang Provincial Natural Science Foundation of China (LQ20H110003), and Foundation of Zhejiang Provincial Education Department (Y201942035).

Conflicts of interest

There are no conflicts of interest.

 

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  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6]
 
 
  [Table 1], [Table 2]

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