Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling

doi:10.21203/rs.3.rs-2800948/v1

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Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling

https://doi.org/10.21203/rs.3.rs-2800948/v1

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published 25 Nov, 2023

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Psoriasis is a chronic inflammatory skin disease that affects millions of people worldwide. Sulforaphane (SFN) has been shown to have anti-inflammatory and antioxidant properties. In this study, we investigated the effects of SFN on a mouse model of psoriasis induced by imiquimod (IMQ) and its underlying molecular mechanism. Mice treated with SFN showed significant improvement in psoriatic symptoms, including reduced erythema, scales, and cutaneous thickness. Histopathological analysis and immunohistochemical staining revealed decreased expression of K16, K17, and Ki67 in SFN-treated mice, indicating reduced abnormal differentiation of keratinocytes and cutaneous inflammation. SFN treatment also reduced the activation of STAT3 and NF-κB pathways and downregulated pro-inflammatory cytokines IL-1β, IL-6, and CCL2. In vitro experiments using HaCaT cells demonstrated that SFN inhibited IL-22 and TNF-α-induced activation of inflammatory pathways and keratinocyte proliferation. Network pharmacology analysis suggested that the KEAP1-NRF2 pathway might be involved in the protective effects of SFN on psoriasis. We observed reduced NRF2 expression in human psoriatic lesions, and subsequent experiments showed that SFN activated KEAP1-NRF2 pathway in vivo and in vitro. Importantly, Nrf2-deficient mice exhibited aggravated psoriasis-like symptoms and reduced response to SFN treatment. Our findings indicate that SFN ameliorates psoriasis symptoms and inflammation through the KEAP1-NRF2 pathway, suggesting a potential therapeutic role for SFN in the treatment of psoriasis.

Health sciences/Pathogenesis/Inflammation/Chronic inflammation

Biological sciences/Cell biology

Psoriasis

Sulforaphane

ROS

KEAP1-NRF2 pathway

Inflammation

Psoriasis is a common long-lasting cutaneous inflammatory disease that affects 3–4% of the global population. Its clinical symptoms are typically red patches with white scales on the top, which appear on the elbows, knees, scalp, and back [1]. It is widely accepted that multiple factors, including genetics and environment, contribute to the pathological development of psoriasis, but its etiology is complex and poorly understood [2].

Oxidative stress is a risk factor for this dermatosis [3]. Oxidative stress refers to a state where there is an elevated production of reactive oxygen species (ROS) or reactive nitrogen species (RNS), coupled with a reduced concentration or diminished activity of antioxidants responsible for neutralizing these reactive species. ROS can damage DNA, proteins, and lipids and activate a variety of inflammatory pathways, all of which contribute to psoriatic inflammation [4, 5]. Patients with psoriasis have increased ROS production and decreased antioxidant capacity [6]. In addition, the severity and duration of the disease are correlated with the level of oxidative stress in the body [7]. The production of ROS and free radicals exacerbates inflammation and hyperplasia of keratinocyte cells [8]. In turn, keratinocytes, activated neutrophils, and lymphocytes in the skin lesions of psoriasis result in the generation of abundant amounts of ROS and free radicals [9]. Therefore, supplementation with exogenous antioxidants represents a useful adjunct option in the treatment of psoriasis.

Sulforaphane (SFN) is a natural isothiocyanate group of organosulfur compounds presents in cruciferous vegetables. In recent years, it has been extensively studied for its potent therapeutic effects on diseases and low cytotoxicity. The antioxidant properties of SFN have been demonstrated to inhibit cell proliferation, activate caspases, induce apoptosis, and stop the cell cycle [10–12]. In a variety of cancers and chronic inflammatory diseases, SFN has been proven to have promising therapeutic effects [13, 14]. Mechanistic studies indicated that SFN regulated the expression of various tumor suppressor genes or inflammatory genes by targeting the HDAC, DNMT, and NF-κB signaling pathways. Additionally, NRF2 and several microRNAs have been shown to be regulated by SFN [13, 15]. However, the functional role and the involved mechanism of SFN in psoriasis are not known and still need to be defined.

In the present study, we aimed to investigate the modulatory effects of SFN in imiquimod (IMQ)-induced psoriatic mice, as well as the underlying molecular mechanisms. We found that decreased NRF2 expression and activation resulted in increased oxidative stress in psoriatic lesional skin. The application of SFN significantly protected cutaneous inflammation in an NRF2-dependent manner. Our data provide crucial experimental evidence that SFN could be used as a therapeutic compound for the treatment of psoriasis.

Skin specimens from psoriasis patients and healthy donors

Skin biopsy specimens were procured from five individuals recently diagnosed with psoriasis and five healthy participants undergoing cosmetic plastic surgery procedures. Diagnoses were made through a combination of clinical assessments and histological analyses, with none of the patients having received any systemic or topical treatments for a minimum of 2 weeks prior to the biopsy. The research protocol received ethical clearance from the Institutional Review Board of the First Affiliated Hospital of Nanjing Medical University. All those contributing skin samples provided informed written consent, and both the patients and volunteers expressed agreement for the publication of their photographs.

IMQ-induced psoriatic mouse model

Six-week-old female BALB/C mice or C57BL/6 mice, along with Nrf2 knockout mice (acquired from the Model Animal Research Center of Nanjing University), were maintained in an SPF environment, subjected to a 12-hour light/dark cycle, and provided with unrestricted access to food and water. The Nanjing University Institutional Animal Ethics Committee granted approval for all animal experiments. The IMQ-induced psoriasis mouse model was developed according to previously established methods. In brief, the mice were administered a daily topical application of 62.5 mg of 5% imiquimod cream (Mingxinlidi, Sichuan, China) on their shaved backs for seven consecutive days. The same amount of vaseline cream was used on control mice and the SFN alone group. SFN (MedChemExpress, NJ, USA) was intraperitoneally injected at 5 mg/kg once a day for 7 consecutive days. The same dose of normal saline was used on control mice and IMQ-induced psoriatic mice. The severity of cutaneous inflammation was scored 24 hours after the last drug administration using the clinical Psoriasis Area and Severity Index (PASI). The mice were euthanized by cervical dislocation and skin tissues, spleen and blood samples were obtained for further experiments.

Western blot analysis

To quantify the protein samples, tissue homogenates and cells were homogenized and quantified using a BCA kit (Beyotime, Shanghai, China). The protein samples were separated using 10% SDS-polyacrylamide gels and transferred to PVDF membranes in equal amounts. After incubating with 5% bovine serum albumin for 1 h, the membranes were incubated with primary antibodies overnight at 4°C. Antibodies used were: anti-keratin 16 (sc-53255, Santa Cruz); anti-keratin 17 (ab53707, Abcam, Cambridge, UK), anti-NRF2 (#12721, Cell Signaling Technologies, MA, USA), anti-phospho-NRF2 (AF1609, Beyotime, Shanghai, China), anti-IL-1β (#12703, Cell Signaling Technologies, MA, USA), anti-NQO1 (AF7614, Beyotime, Shanghai, China), anti-phospho-STAT3 (Tyr705) (#9145, Cell Signaling Technology, MA, USA), anti-STAT3 (#12640, Cell Signaling Technology, MA, USA), anti-phospho-NF-κB p65 (#3033, Cell Signaling Technology, MA, USA), anti-NF-κB p65 (#8242, Cell Signaling Technology, MA, USA), anti-phospho-IκBα (#2859, Cell Signaling Technology, MA, USA), anti-IκBα (#4812, Cell Signaling Technology, MA, USA) and GAPDH (BS60630, Bioworld Technology Inc., MN, USA). Blots were incubated with HRP-conjugated secondary antibodies (BS13278, Bioworld Technology Inc., MN, USA) for 1 h, and protein expression was detected with ECL (WBULS0500, Millipore, MA, USA) by digital imaging systems (SYNGENE, Cambridge, UK). ImageJ software was used to analyze the density of the western blot results.

Histopathological examination and immunofluorescence staining

The dorsal skin was preserved in 10% buffered formalin for a duration of 24 hours before being embedded in paraffin wax. Paraffin-embedded samples were sectioned into 3-micrometer-thick slices and mounted onto glass slides. These slides were then subjected to hematoxylin and eosin (H&E) staining and immunohistochemical analysis, adhering to the guidelines outlined in the AFIP Laboratory Methods in Histotechnology manual. The streptavidin-peroxidase technique was employed for immunostaining. Primary antibodies used included anti-keratin 16 (sc-53255, Santa Cruz), anti-Ki67 (ab16667, Abcam, Cambridge, UK), anti-keratin 17 (ab53707, Abcam, Cambridge, UK), and anti-NQO1 (AF7614, Beyotime, Shanghai, China).

Real-Time Quantitative Reverse Transcription PCR (qRT‒PCR) Analysis

Total RNA from skin tissues was isolated using TRIzol reagent (Sigma, Milwaukee, WI, USA), and 1 µg of total RNA was reverse-transcribed into cDNA. All qPCR assays were performed on the QuantStudio 5 Real-Time PCR system (Applied Biosystems, CA, USA) with Power-Up SYBR Master Mix (Applied Biosystems, CA, USA). The relative expression of the target genes was normalized to that of β-actin and calculated with the 2ΔΔCt method. The primer sequences of the target and control genes were as follows: IL-6 forward: 5′-ACAAAGCCAGAGTCCTTCAGAG-3′ and reverse, 5′-GGTCCTTAGCCACTCCTTCTG-3′; IL-1β forward: 5′-TCCAGGATGAGGACATGAGCA-3′ and reverse, 5′-GAACGTCACACACCAGCAGGT-3′; CCL2 forward: 5′-TTAAAAACCTGGATCGGAACCAA-3′ and reverse, 5′-GCATTAGCTTCAGATTTACGGGT-3′; β-actin forward: 5′-CTAAGGCCAACCGTGAAAAG-3′ and reverse, 5′- ACCAGAGGCATACAGGGACA-3′.

Cell culture and treatment

Immortalized human keratinocyte (HaCaT) cells (NE Fusenig, Heidelberg, Germany) were cultured in adipocyte medium (AM, high-glucose DMEM with 10% FBS and 1% P/S) at 37°C in a humidified incubator with 5% CO₂. HaCaT cells were treated with IL-22 (25 mmol/L; 13059-HNAE, Sino Biological, China) or TNF-α (25 mmol/L; 10602-H01H, Sino Biological, China) for 30 minutes or 24 h to establish a psoriasis-like keratinocyte model.

Measurements of intracellular ROS

After treatment with IL-22 (25 ng/ml) and/or SFN (20 nM), HaCaT cells were harvested and stained with 2 µM dihydroethidium (DHE, Beyotime Institute of Biotechnology) for 30 min at 37°C in the dark. The fluorescence intensity was assayed by an FV10i laser scanning confocal microscope (Olympus, Tokyo, Japan).

Target analysis of sulforaphane in psoriasis

To study the molecular mechanism by which SFN alleviates psoriasis, network pharmacology was performed using the SuperPred(https://prediction.charite.de/) and OMIM (https://www.omim.org/) databases to predict the target molecules of SFN. The target molecules were converted to genes and intersected with psoriasis-related genes from GeneCards (https://www.genecards.org/) and OMIM. The PPI network of the target genes was created using STRING (https://cn.string-db.org/), and the pathways were assessed via Reactome analysis for enrichment. The expression levels of NRF2 were evaluated using the Human Protein Atlas portal website (http://www.proteinatlas.org/) and the GEO database.

Statistical analyses

Statistical analyses were conducted using GraphPad Prism software (version 9.0.0). Dual comparisons were unpaired Student's t-tests, and multigroup comparisons were made with one-way analysis of variance (ANOVA). The results of three independent experiments are presented as the mean ± standard deviation (SD), and p < 0.05 was considered statistically significant.

SFN ameliorates psoriatic symptoms in IMQ-induced psoriatic mouse model

To investigate the functional role of SFN in psoriasis, a mouse model of IMQ-induced psoriasis treated with systemic SFN was used (Fig. 1A). Mice that received 5% IMQ cream applied to shaved dorsal skin daily for seven consecutive days developed a distinct psoriasis-like appearance (Fig. 1B, left panel). Psoriatic mice treated with SFN, however, showed a significant decrease in IMQ-induced psoriatic traits, such as erythema, scales, and cutaneous thickness. Furthermore, mice treated with SFN had fewer psoriasiform lesions (Fig. 1B, left panel). The PASI scores calculated and plotted on day 8 are shown in Fig. 1C. Moreover, SFN treatment significantly reduced the overall PASI score compared with the IMQ group, indicating the protective effects of SFN on psoriasis.

To further evaluate the role of SFN in the IMQ-induced psoriasis mouse model, histopathological analysis of mouse dorsal skin was performed by H&E staining (Fig. 1B, right panel). Mice in the IMQ group developed typical psoriasis-like changes, such as Munro microabscesses in the corneum, hyperkeratosis and hyperkeratosis in the epidermis, spinous layer thickening, regularly elongated rete ridges, and lymphocytic infiltration in the dermis (Fig. 1B, right panel). In contrast, the SFN-treated group showed remarkable improvement in epidermal thickness and infiltrating cells (Fig. 1B, right panel), although no significant difference was observed in spleen size (Fig. 1D).

Psoriatic mice treated with SFN exhibit decreased keratinocyte differentiation and reduced cutaneous inflammation

Keratin 16 (K16) and keratin 17 (K17) are established markers of excessive keratinocyte hyperproliferation in psoriasis and are known to promote T-cell activation and psoriasis development [16, 17]. Ki67 serves as a cell proliferation marker for keratinocytes [18]. We investigated the expression of K16, K17, and Ki67 in mouse skin tissues using immunohistochemical staining. Our findings demonstrated that the SFN treatment group exhibited significantly lower expression of K16, K17, and Ki67 compared to the IMQ group (Fig. 2A). Moreover, SFN treatment notably decreased the elevated protein expression levels of K16 and K17 (Fig. 2B, C).

Persistent STAT3 activation, a recognized potential target in psoriasis, is crucial in psoriasis pathogenesis. Furthermore, NF-κB is a key transcription factor in immune response, with numerous downstream genes in the NF-κB pathway contributing to psoriasis' pathological development [19, 20]. To examine the impact of SFN on inflammatory pathways in psoriatic mouse skin, we measured the expression levels of p-STAT3 and p-IκBα. The IMQ group displayed significantly increased expression levels of p-STAT3 and p-IκBα. In contrast, SFN treatment considerably diminished the expression levels of p-STAT3 and p-IκBα in psoriatic mouse skin (Fig. 2B, C).

To further verify whether SFN could modulate the expression of inflammatory factors and chemokines during psoriasis development, we evaluated the mRNA levels of IL-1β, IL-6, and CCL2 using qPCR. IL-1β, which is secreted by macrophages and has a vital role in psoriasis immunity [21], and IL-6, which activates the JAK-STAT pathway and exhibits elevated levels in psoriasis patients' lesions [22], were both significantly increased in psoriasis-induced mice. However, SFN treatment substantially reduced IL-1β and IL-6 mRNA expression levels (Fig. 2D). Additionally, CCL2, a neutrophil chemokine implicated in angiogenesis and the pathological changes of psoriatic lesions [23], was markedly elevated in psoriasis-induced mice. SFN treatment effectively decreased the mRNA expression of CCL2 compared to psoriasis-induced mice (Fig. 2D). These findings highlight the efficacy of SFN treatment in attenuating keratinocyte hyperproliferation and cutaneous inflammation in psoriatic mice by regulating the expression of crucial inflammatory markers and chemokines, indicating its potential therapeutic value in managing psoriasis.

SFN mitigates TNF-a and IL-22-induced activation of inflammatory pathways and proliferation in HaCaT cells

IL-22 is known to bind to the IL-22 receptor on keratinocytes, induce STAT3 phosphorylation, and promote keratinocyte proliferation [24, 25]. Considering the significant role of IL-22 in psoriasis pathogenesis, we added IL-22 (25 mM) to HaCaT cells treated with or without SFN. We then detected the protein expression levels of STAT3, p-STAT3, K16, and K17 using western blot analysis. Our results revealed that SFN treatment considerably inhibited the phosphorylation of STAT3 and the expression of K16 and K17 (Fig. 3A, B).

TNF-α-induced NF-κB pathway activation plays a part in psoriasis, and TNF-α monoclonal antibodies have been employed in clinical settings for psoriasis treatment [26]. To investigate the impact of SFN, HaCaT cells were treated with TNF-α (25 mM). In line with previous findings, SFN impeded TNF-α-induced phosphorylation of IκB and significantly decreased IL-1β expression. Additionally, TNF-α stimulated the expression of K16 and K17, whereas SFN suppressed their expression (Fig. 3C, D). These results suggest that SFN exerts an inhibitory effect on both the STAT3 and NF-κB signaling pathways.

SFN alleviates psoriasis via the KEAP1-NFE2L2 pathway

Given the observed therapeutic effects of SFN, we sought to investigate the potential molecular mechanisms responsible for the therapeutic effect. Network pharmacology was employed to investigate the molecular mechanism of SFN in treating psoriasis. Using the SuperPred and OMIM databases, 113 target molecules were identified (Fig. 4A) and converted to corresponding genes, which were then cross-referenced with psoriasis-related genes from GeneCards and OMIM. Forty-nine target genes were found (Fig. 4B). The PPI network was constructed with STRING (Fig. 4C), and Reactome pathway analysis in Clue go was utilized to evaluate the target genes. Four significant pathways were identified: CRMPs in Sema3A signaling, KEAP1-NFE2L2 pathway, Purinergic signaling in leishmaniasis infection, and Collagen degradation (Fig. 4D). The KEAP1-NFE2L2 pathway, with the most enriched genes, was selected for further study.

NRF2 is a bZIP protein involved in regulating oxidative stress, inflammation, autophagy, and immune response. NRF2 is anchored in the cytoplasm under normal conditions but enters the nucleus and activates antioxidant genes during oxidative stress [27, 28]. We used the Human Protein Atlas and GEO database to observe NRF2 expression in various organ tissues, including skin, and found decreased NRF2 expression in psoriatic lesions (Fig. 5A, B). qPCR and immunofluorescence confirmed reduced NRF2 RNA and protein expression in psoriatic lesions compared to normal skin (Fig. 5C, D). In vivo treatment with SFN resulted in higher NRF2 and p-NRF2 expression in SFN-treated mice compared to IMQ-induced psoriatic mice (Fig. 6A-C). In vitro, SFN pretreatment restored NRF2 and p-NRF2 expression in IL-22-treated and TNF-α-treated HaCaT cells (Fig. 7A, B). Moreover, SFN treatment reduced IL-22-induced superoxide production (Fig. 7C). These findings suggest that NRF2 has a protective role in psoriasis and that SFN enhances NRF2 and p-NRF2 expression.

Nrf2 depletion exacerbates IMQ-induced psoriasis-like symptoms and negates the therapeutic effect of SFN

To further investigate the mechanism of SFN, we utilized both wild-type and Nrf2-deficient mice for modeling and treatment. On days 4 and 8, Nrf2-deficient mice displayed more severe lesions that did not show significant improvement following SFN treatment (Fig. 8A, B). Additionally, in the skin of Nrf2-deficient psoriasis-like mice, the STAT3 and NF-κB pathways were activated, and K16 expression increased (Fig. 8C, D). NAD(P)H dehydrogenase (NQO1), an NRF2-targeted enzyme possessing broad cytoprotective functions [29], was upregulated in the skin tissues of IMQ-induced psoriatic mice treated with SFN, whereas Nrf2-deficient mice exhibited minimal expression (Fig. 8C, D). We utilized immunohistochemistry to detect K16, K17, and Ki67, observing mouse skin keratinocyte proliferation as in previous mouse experiments. Consistent with our expectations, Nrf2 depletion promoted the cell cycle and proliferation of keratinocytes. Furthermore, SFN treatment did not yield significant differences (Fig. 8E). These findings suggest that the therapeutic effect of SFN on IMQ-induced mice is primarily dependent on NRF2 activation, and that NRF2 deletion exacerbates psoriasis-like skin lesions.

Bioactive compounds found in nature have great potential for treating diseases and may be safer in than synthetic agents [30, 31]. SFN is a natural isothiocyanate compound derived from plants, mainly from cruciferous vegetables such as cabbage, broccoli, cauliflower, and hugger kale, with a promising biosafety profile [32]. Previous studies have shown that SFN has antioxidant, antineoplastic, antiangiogenic, anti-inflammatory, and antibacterial properties [13, 33]. However, its function in psoriasis is poorly understood. Therefore, our current study aimed to investigate its therapeutic potential in psoriasis. Our study confirmed that SFN can be effective against cutaneous inflammation in an IMQ-induced psoriatic mouse model, consistent with previous findings of its therapeutic effects in chronic inflammatory diseases such as inflammatory bowel disease, respiratory diseases, and rheumatoid arthritis [34].

The current study found that SFN reduces psoriatic inflammation most likely due to its antioxidant properties. Several studies have found that oxidative stress is a significant contributor to psoriasis pathogenesis. Specifically, an imbalance between oxidants and antioxidants, increased ROS production, a reduction in antioxidant enzymes function contribute to the pathogenesis and development of psoriasis[3]. Oxidative stress biomarkers can be used to assess psoriasis severity, predict treatment outcome, and forecast comorbidities. Psoriasis symptoms are exacerbated by a variety of external pro-oxidative stress factors, including narcotics, smoking, drinking alcohol, stress, and bacterial infections.[35, 36]. In our study, we demonstrated that SFN significantly alleviated psoriasis-associated oxidative stress injury, indicating its antioxidant properties.

To explore the molecular mechanism of SFN-mediated antioxidative protection, network pharmacology was used to predict the therapeutic targets of SFN in psoriasis. There were four enriched pathways identified in the pathway enrichment analysis, and the top-ranked pathway was KEAP1-NFE2L2. The KEAP1/NRF2 pathway demonstrates antioxidative and anti-inflammatory properties and plays a crucial role in maintaining skin homeostasis. Our study revealed that NRF2 is highly expressed in healthy skin, which aligns with findings reported in public databases [37]. NRF2 activation emerges as a promising therapeutic approach for a range of skin disorders. Notably, we detected a marked reduction in NRF2 expression in the lesioned skin of both clinical biopsy samples and the IMQ-induced psoriatic mouse model. SFN treatment significantly restored the expression of NRF2 and alleviated the psoriatic pathological phenotype by blocking oxidative stress-induced skin tissue damage and cutaneous inflammation. The protective effect of SFN appears to be NRF2-dependent, as NRF2 deficiency exacerbated psoriasis-like symptoms, as well as the inflammatory response and abnormal proliferation of keratinocytes in the mice, and SFN had little therapeutic effect in the IMQ-modeled knockout mice. This finding supports our hypothesis that NRF2 plays a protective role in the development of psoriasis and that SFN acts via NRF2-related pathways. In in vitro experiments, NRF2 expression was reduced in IL-22-stimulated HaCaT cells, while the addition of SFN partially restored NRF2 expression. We also noticed that SFN treatment reduced IL-22-induced ROS production in HaCaT cells.

Another important mechanism for SFN-mediated immune protection against psoriatic inflammation is its function in the regulation of inflammatory pathway activation. JAK2/STAT3 has recently been recognized as a key inflammatory pathway in the development and pathogenesis of psoriasis. STAT3 not only involved in promoting Th17 cell differentiation but also directly activates IL-17 [38]. TNF-α/NF-κB pathway is another important inflammatory pathway in the development of psoriasis. Inhibitors of this pathway, such as etanercept, infliximab, and adalimumab, have proven effective in clinical practice [39]. In our study, we treated psoriasis-induced mice and IL-22- or TNF-α-stimulated HaCaT cells with SFN and subsequently measured the activation status of the STAT3 and NF-κB pathways. Our results demonstrated a significant reduction in inflammatory pathway activation in both the IMQ-induced psoriasis mouse model and the in vitro cell model. Another characteristic of psoriasis is the excessive proliferation and aberrant terminal differentiation of keratinocytes. The upregulation of K16 and K17 in keratinocytes plays a crucial role in modulating the proliferation, migration, and inflammatory response of keratinized cells [40, 41]. As a result, K16 and K17 are generally considered as biomarkers and potential therapeutic targets for psoriasis. We assessed keratin expression and found that the elevated expression of K16 and K17 diminished in both in vivo and in vitro experiments following SFN treatment. In line with these findings, we discovered that SFN could inhibit the expression of IL-6 and IL-1β, both of which are regulated by NRF2 [42, 43].

Our study reveals that reduced expression of NRF2 contributes to oxidative stress injury, which plays a role in the pathogenesis of psoriasis. Treatment with SFN activates the NRF2 signaling pathway, mitigating oxidative stress injury and attenuating the inflammatory response associated with psoriasis. These findings suggest that SFN holds promise as an effective therapeutic agent for alleviating cutaneous inflammation in psoriasis.

Data availability

The data used to support the findings of this study are included within the article.

Conflict of interest

The authors declare that they have no conflict of interest.

Authors’ contributions

Chujun Ma: Conceptualization, Methodology, Formal analysis, Writing - Original Draft Ziqi Peng: Methodology, Validation, Formal analysis Panpan Lian: Methodology, Validation Junaid Wazir: Writing - Review & Editing Renwei Lu: Validation, Formal analysis Chaode Gu: Formal analysis Lulu Wei: Methodology Li Li: Validation Wenyuan Pu: Validation Zhonglan Su: Supervision Yan Lu: Supervision Hongwei Wang: Conceptualization, Resources, Writing - Review & Editing

All data were generated in house, and no paper mill was used. All authors agree to be accountable for all aspects of the work ensuring integrity and accuracy.

Acknowledgments

We thank Prof Wangsen Cao for their critical review and thoughtful discussion of the manuscript.

Conflict of interest

The authors declare no conflict of interest. The sponsors had no role in the design, execution, interpretation, or writing of the study.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Nos. 82070912 and 81773326), and the Natural Science Foundation of Jiangsu Province, China (No. BE2019676).

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published 25 Nov, 2023

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Sulforaphane alleviates psoriasis by enhancing antioxidant defense through KEAP1-NRF2 Pathway activation and attenuating inflammatory signaling

Status:

Journal Publication

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Abstract

Figures

INTRODUCTION

METHODS

Skin specimens from psoriasis patients and healthy donors

IMQ-induced psoriatic mouse model

Western blot analysis

Histopathological examination and immunofluorescence staining

Real-Time Quantitative Reverse Transcription PCR (qRT‒PCR) Analysis

Cell culture and treatment

Measurements of intracellular ROS

Target analysis of sulforaphane in psoriasis

Statistical analyses

RESULTS

SFN ameliorates psoriatic symptoms in IMQ-induced psoriatic mouse model

Psoriatic mice treated with SFN exhibit decreased keratinocyte differentiation and reduced cutaneous inflammation

SFN mitigates TNF-a and IL-22-induced activation of inflammatory pathways and proliferation in HaCaT cells

SFN alleviates psoriasis via the KEAP1-NFE2L2 pathway

Nrf2 depletion exacerbates IMQ-induced psoriasis-like symptoms and negates the therapeutic effect of SFN

DISCUSSION

Conclusion

Declarations

References

Additional Declarations

Status:

Journal Publication

Version 1