Psoriasis Model Research Articles

Identification of a Chemical Probe for BLT2 Activation by Scaffold Hopping.

The leukotriene B4 receptor 2 (BLT2) is a G-protein coupled receptor, which is endogenously activated by 12(S)-hydroxyheptadeca-5Z,8E,10E-trienoic acid (12-HHT). BLT2 is gaining attention as a potential therapeutic target involved in various pathologies including diabetic wound healing, ophthalmic diseases, and colitis. However, validation of BLT2 as drug target requires chemical probes and pharmacological tools which will allow for application in vivo. In this work, we present the discovery of a novel chemical probe T-10430 for BLT2 agonism following a scaffold-hopping approach. T-10430 exhibits high potency, good selectivity profile, promising physicochemical and PK properties and can potentially serve as orally applicable pharmacological tool for validation of BLT2 as drug target. Using T-10430, we demonstrate the beneficial effect of BLT2 activation in mouse model of psoriasis.

Guggulsterone ameliorates psoriasis by inhibiting keratinocyte proliferation and inflammation through induction of miR-17 directly targeting JAK1 and STAT3.

The pathogenesis of psoriasis involves hyperproliferation of epidermal keratinocytes and abnormal interactions between activated keratinocytes and infiltrating immune cells. Emerging evidence has shown that keratinocytes play essential roles in both the initiation and maintenance of psoriasis, suggesting that exposing keratinocytes to agents with antiproliferative and anti-inflammatory effects may be effective for psoriasis treatment. Guggulsterone (GS), a plant sterol derived from the gum resin of Commiphora wightii, possesses a variety of pharmacological activities. However, the effects of GS on psoriasis and the underlying mechanism have not been elucidated. In this study, we evaluated the therapeutic effect of GS on psoriasis using an imiquimod-induced psoriasis mouse model and investigated the effect of GS on human keratinocytes and the underlying mechanism. We found that GS effectively alleviated psoriasis-like skin lesions in imiquimod-induced psoriasis model mice and that GS suppressed the proliferation, migration, and production of proinflammatory cytokines, chemokines and antimicrobial peptides in keratinocytes. Transcriptome analysis by RNA-seq revealed that the differentially expressed genes (DEGs) induced by GS in keratinocytes were intricately linked to the pathogenesis of psoriasis. Furthermore, STAT3, a key player in the development and pathogenesis of psoriasis, was identified as a critical downstream mediator of GS in keratinocytes. Mechanistically, GS upregulated the expression of miR-17-5p, which directly binds to the 3'-untranslated regions (3'UTRs) of JAK1 and STAT3, leading to the downregulation of JAK1 and STAT3 expression. Collectively, these findings suggest that GS may serve as an effective natural compound for the treatment of psoriasis.

SIRT6 knockdown alleviates keratinocyte hyperproliferation and inflammation in psoriasis via modulating acetylation of FOXO1.

The Sirtuins family (SIRT) has been implicated in numerous diseases, including psoriasis.However, the precise role of SIRT6 in psoriasis remains unclear. The analysis of publicly available RNA-seq data from GEO profiles showed that SIRT6 expression levels was significantly elevated in the lesional skins from patients with psoriasis, as compared to the non-lesional skins or the skins from normal healthy donors. It was also confirmed that SIRT6 and Ki67 expression was consistently upregulated inpsoriatic lesional skin,mouse models of psoriasis established by imiquimod treatment, and HaCat cells treated with M5. When SIRT6 was knocked down or inhibited in M5-treated HaCat cells, there was a significant suppression ofM5-induced increases in inflammatory cytokines such as interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α. The upregulation of Ki67 expression and cell proliferation induced by M5 were also reduced. SIRT6 inhibitor also significantly reduced the epidermal thickness and Ki67 expression levels in mouse models of psoriasis. Mechanistically, SIRT6 knockdown or inhibition enhanced the nuclear translocation of forkhead box O 1 (FOXO1) by increasing its acetylation level. M5 treatment reduced the nuclear FOXO1 levels via enhancing the nuclear efflux of Foxo1. Knockdown or inhibition of SIRT6 resulted in an increase in nuclear FOXO1 levels, not through enhancing its nuclear influx, but possibly by impeding the nuclear efflux of Foxo1. In conclusion, the knockdown of the SIRT6 promoted the nuclear translocation of FOXO1 by upregulating its acetylation level, thereby inhibiting M5-induced hyperproliferation and inflammation of keratinocyte. Given the crucial role of SIRT6 in psoriasis, it may represent a promising target for the development of small-molecule inhibitors with therapeutic potential for psoriasis.

Limonin alleviates imiquimod-induced psoriasis-like skin inflammation in mice model by downregulating inflammatory responses.

Psoriasis is a chronic inflammatory condition affecting 1-2% of the global population. Phytomedicine, which uses plant-based compounds, is emerging as a promising approach to managing such inflammatory diseases. Limonin, a phytochemical found in citrus fruits and known for its bitter taste, possesses significant pharmacological properties. In this study, we evaluated the anti-psoriatic effects of limonin using a psoriasis-induced mice model. BALB/c mice were treated with imiquimod to induce psoriasis and then administered limonin at doses of 20 and 40 mg/kg/day for 6 days. Tacrolimus ointment served as a positive control. We assessed the hematological profile to determine limonin's impact on leukocytes in the psoriasis model. Additionally, histomorphometric analysis of ear and skin tissues was conducted to evaluate the therapeutic effects of limonin. We further investigated the antioxidant properties of limonin by measuring levels of antioxidants and oxidative stress markers. The anti-inflammatory effects were evaluated by quantifying inflammatory cytokines and signaling proteins. In vitro, the cytotoxicity and anti-inflammatory potential of limonin were assessed using murine macrophage RAW264.7 cells. Our findings showed that limonin significantly reduced leukocyte counts, decreased inflammatory cell infiltration, and improved skin histoarchitecture in psoriasis-induced mice. Limonin also effectively scavenged free radicals and reduced levels of inflammatory cytokines and proteins without causing cytotoxicity in RAW264.7 cells. Overall, our in vivo and in vitro results confirm that limonin is a potent anti-inflammatory agent that effectively ameliorates imiquimod-induced psoriasis.

Photoswitchable Diazocine Derivative for Adenosine A3 Receptor Activation in Psoriasis.

Incorporating photoisomerizable moieties within drugs offers the possibility of rapid and reversible light-dependent switching between active and inactive configurations. Here, we developed a photoswitchable adenosine A3 receptor (A3R) agonist that confers optical control on this G protein-coupled receptor through noninvasive topical skin irradiation in an animal model of psoriasis. This was achieved by covalently bonding an adenosine-5'-methyluronamide moiety to a diazocine photochrome, whose singular photoswitching properties facilitated repeated interconversion between a thermally stable, biologically inactive Z agonist form and a photoinduced, pharmacologically active E configuration. As a result, our photoswitchable agonist allowed the precise modulation of A3R function both in vitro and in vivo, which led to a clear light-controlled pharmacotherapeutic effect on mouse skin lesions. This breakthrough not only demonstrates the potential of diazocine photoswitches for in vivo photopharmacology but also paves the way for the development of new strategies for skin-related diseases that require localized and temporally controlled drug action.

A novel monoclonal antibody against human thymic stromal lymphopoietin for the treatment of TSLP-mediated diseases.

Thymic stromal lymphopoietin (TSLP) is a master regulator of allergic inflammation against pathogens at barrier surfaces of the lung, skin, and gut. However, aberrant TSLP activity is implicated in various allergic, chronic inflammation and autoimmune diseases and cancers. Biologics drugs neutralizing excess TSLP activity represented by tezepelumab have been approved for severe asthma and are being evaluated for the treatments of other TSLP-mediated diseases. In this study, we discovered and characterized a novel humanized anti-TSLP antibody TAVO101 with high binding affinity to human TSLP, which blocks TSLP binding to its receptor complexes on cell surface. TAVO101 showed potent neutralization of TSLP activities in the TSLP-driven STAT5 reporter assay and cell proliferation assay. Results from ex vivo studies showed that TAVO101 neutralized TSLP-mediated CCL17 release from primary human CD1c+ dendritic cells and proliferation of activated CD4+ T cells. In addition, TAVO101 showed strong efficacy in both TSLP/OVA-induced asthma and imiquimod induced psoriasis models in hTSLP/hTSLPR double knock-in mice. We further conducted Fc engineering to optimize TAVO101 antibody with reduced affinity to Fcγ receptors and C1q protein but with increased affinity to FcRn receptor for half-life extension. By recognizing a different epitope, similarly potent neutralization of TSLP activities, and longer circulating half-life than tezepelumab, novel anti-TSLP antibody TAVO101 offers a potential best-in class therapeutics for various TSLP-mediated diseases.

P94 REX-7117 is a highly potent and selective oral STAT3 inhibitor that has demonstrated potential efficacy and safety differentiation versus JAK/TYK2 targeting in preclinical models of psoriasis

Abstract Inhibition of key cytokine pathways, including IL-23 and IL-17, has translated into transformative efficacy in plaque psoriasis, psoriatic arthritis and other inflammatory diseases. There is a strong unmet need to develop oral medicines which match the efficacy of biologics. Additionally, current small molecule JAK/TYK2 inhibitors are associated with on-target safety signals, including opportunistic infections and dysregulated haematologic homeostasis (anaemia, thrombocytopenia). Oral selective STAT3 inhibitors represent an opportunity to target psoriatic pathogenesis by inhibiting clinically validated inflammatory mediators, such as IL-23 and IL-6 cytokines. The STAT3 SH2 domain mediates both binding to the cytokine receptor and transcriptional activity, and therefore is an attractive therapeutic target. Recludix has developed an innovative and proprietary SH2 domain platform that has enabled the discovery of a new class of small molecule inhibitors of these previously undruggable protein domains. REX-7117 is the first orally available, reversible, SH2 domain-targeting STAT3 inhibitor. REX-7117 demonstrates low nanomolar potency in biochemical and primary human cellular assays, is highly selective across the SH2 family, including other STAT proteins, and inhibits IL-6 and IL-23 driven Th17 cell function. Unlike JAK1/2 and TYK2 inhibitors, REX-7117 does not impair broader immune responses, such as Th1 cell activity, innate interferon-dependent anti-viral immunity, or growth factor signalling critical for haematologic homeostasis. In dogs and mice, REX-7117 achieves deep, durable, and selective STAT3 inhibition at clinically relevant oral doses and exhibits comparable efficacy to an IL-17 antibody in rodent models of plaque psoriasis. Selective STAT3 inhibition has the potential to combine the efficacy of clinically validated biologics with the convenience of oral administration, while avoiding known safety concerns observed with the broader activity of JAK and TYK2 inhibitors.

Indoleamine-2,3-dioxygenase (IDO) Mediates the Suppression of T Cells by IFN-γ Primed Mesenchymal Stromal Cells in the Treatment of Psoriasis-Like Inflammation.

Psoriasis is a chronic and incurable skin inflammation driven by an abnormal immune response. Our study aims to investigate the potential of interferon-γ (IFN-γ) primed mesenchymal stem cells (IMSCs) in targeting T cells to attenuate psoriasis-like inflammation, and to elucidate the underlying molecular mechanism involved. Mesenchymal stem cells (MSCs) were isolated from the umbilical cord and identified based on their surface markers. Psoriasis models were established and then treated with IMSCs. Flow cytometry analysis was used to examine cell surface markers and T cell percentages. Indoleamine-2,3-dioxygenase (IDO) was knocked down by small interfering RNA (siRNA) and examined with western blot assay. The proliferative capacity of T cells was assessed using water-soluble tetrazolium salt-1(WST-1). Additionally, an immunohistochemical assay was used to determine epidermal thickness. The psoriasis area and severity index (PASI) scores were also assessed. We observed significant therapeutic efficacy of IMSCs against psoriasis-like inflammation in mice. Treatment with IMSCs resulted in a notable reduction in T cell infiltration within psoriatic lesions. Furthermore, we demonstrated that the therapeutic efficacy was mediated by the upregulation of IDO through IFN-γ stimulation. In vitro, IDO inhibited T cell proliferation, and in vivo, the therapeutic efficacy was eliminated when MSCs were transfected with IDO siRNA. IMSCs can treat psoriasis by suppressing T cell infiltration and the suppression is mediated by IDO.

FC19 A global investigation of the aryl hydrocarbon receptor pathway reveals multiple levels of dysregulation amenable for therapeutic targeting in psoriasis

Abstract The aryl hydrocarbon receptor (AHR) is a ligand-activated transcription factor and environmental sensor with homeostatic roles in the skin. We and others have shown that physiological AHR activation ameliorates inflammation in psoriasis models, leading to the development of the first-in-class AHR-modulating drug, Tapinarof, for mild-to-moderate psoriasis. The AHR pathway is regulated at multiple levels, including through the cytochrome P450 1 (CYP1) enzymes, which degrade AHR ligands providing critical negative feedback. Here we aim to deeply investigate the AHR pathway to identify dysfunctional checkpoints for therapeutic intervention in psoriasis. We performed a multi-model investigation in the blood and skin of White moderate-to-severe psoriasis patients (n = 51), not receiving systemic therapy, and age/sex/ethnicity-matched healthy volunteers (n = 28), assessing AHR ligand and precursor availability in serum, AHR and CYP1A1 bulk and spatial mRNA and protein in blood and skin, in vitro modulation of AHR expression in normal human epidermal keratinocytes (NHEK) by psoriasis-relevant cytokines, and CYP1 enzymatic activity. Serum levels of the ligand precursor tryptophan were significantly decreased in psoriasis patients (P < 0.001; n = 19) vs. healthy (n = 19). AHR mRNA expression was significantly decreased in psoriasis blood (P < 0.01; n = 30) and psoriasis lesional (PsL; P < 0.01; n = 17) skin vs. healthy, while CYP1A1 mRNA expression did not differ in blood but showed a downward trend in PsL (P = 0.0546; n = 16). While AHR and CYP1A1 protein were mostly co-expressed in the suprabasal skin layers, AHR mRNA predominantly localized in the basal layer in PsL (n = 5) compared with a more widespread expression in healthy skin (n = 7), with a reduction in AHR positive cells in the PsL dermis (P < 0.05). TNF (P < 0.001) and IFN-γ (P < 0.0001) significantly upregulated AHR mRNA in NHEK (n = 4). In vitro culture of skin epidermal sheets with the AHR agonist FICZ significantly upregulated CYP1A1 mRNA expression in healthy (q < 0.05; n = 8) and psoriasis epidermis (q < 0.05; n = 7); however, CYP1 enzymatic activity was not increased by AHR ligation in PsL. In contrast, FICZ-induced CYP1 enzymatic activity was enhanced in Th17 cells from the same patients (P = 0.0535; n = 8). Finally, exposure of NHEK to a psoriasis inflammatory cocktail containing TNF, IL-23 and IL-17A resulted in a significant reduction in induced CYP1 enzymatic activity (n = 3, P < 0.05), suggesting a potential mechanism for the lack of ligand-induced activity in PsL. Taken together, our data show that there is a multi-level dysregulation of the AHR pathway in psoriasis and suggests a failure of multiple pathway checkpoints that could be further targeted to restore AHR’s beneficial effects on skin.

FC17 Inducible deletion of Mettl3 in murine keratinocytes induces spontaneous inflammation: a novel model for palmoplantar pustulosis and palmoplantar pustular psoriasis

Abstract Palmoplantar pustulosis (PPP) and palmoplantar pustular psoriasis (PPPP) are chronic inflammatory skin conditions characterized by the eruption of sterile pustules on the palms and/or soles. Although several animal models have been established for plaque psoriasis, no models currently exist for PPP or PPPP. In this study, we demonstrate that the inducible deletion of METTL3, an m6A RNA methyltransferase, in murine keratinocytes results in spontaneous, sterile skin inflammation localized exclusively to the palms, soles, and tail. Histopathological examination revealed intraepidermal accumulation of neutrophils and the formation of subcorneal pustules. Transcriptomic sequencing showed that the gene expression profile of the tail lesions closely resembles that of psoriatic lesions in human patients. In the palm lesions, differential gene expression analysis identified pathways associated with leukocyte chemotaxis, migration, and inflammatory responses. KEGG enrichment analysis highlighted several relevant signalling pathways, including the IL-17 signalling pathway, cytokine-cytokine receptor interaction, TNF signalling pathway, and NF-kappa B signalling pathway, etc. Importantly, inflammation-related genes such as Il1b, Il6, and Il19, along with neutrophil chemotaxis-related genes (Cxcl1, Cxcl2, Cxcl3, Cxcl5, and Cxcl15) and antimicrobial peptides (S100a7/8/9 and Defb4), exhibited significantly elevated expression levels in our model, correlating with findings in patient PPP lesions. RT-qPCR further validated our transcriptomic results, while immunofluorescence staining revealed a substantial accumulation of neutrophils at the lesion sites. This study provides a valuable model and foundational basis for future research into PPP and PPPP, laying the basis for new investigations in this field.

P102 Importance of the inflammation in adipose tissue as exacerbating factor of obesity-associated psoriasis

Abstract Obesity is a risk factor for psoriasis. However, it is not necessarily detrimental when excess fat is stored in healthy adipose tissue. To identify pathogenic association between obesity and psoriasis, we investigated an obese mouse model of psoriasis induced by topical imiquimod or dermal interleukin (IL)-23 injection. Obese mice exhibited aggravated psoriatic dermatitis with pronounced systemic inflammatory responses when exposed to imiquimod. Notably, imiquimod-induced psoriatic dermatitis in obese mice significantly reduced fat mass. Further, pronounced monocyte–macrophage infiltration of perigonadal adipose tissue, increased expression of genes linked to inflammation, and upregulation of cell death-associated molecules were evident in obese mice treated with imiquimod compared with their lean counterparts. In contrast, IL-23 injection could induce similar features of psoriatic inflammation in obese and lean mice, without causing adipose tissue destruction or a systemic increase in inflammatory mediators. Obese adipose tissue of mice with imiquimod-induced psoriatic inflammation featured genetic and epigenetic changes in adipocytes and shifts in macrophage compartments towards disturbed homeostasis using multiomic single-nucleus sequencing targeting RNA and accessible chromatin. Our study demonstrates that disrupted homeostasis in obese adipose tissue amplifies the systemic manifestations of psoriasis, highlighting the potential for developing interventions to control obesity-associated exacerbation of psoriasis.

P42 KLHDC7B participates in the mechanism of UVB treatment for psoriasis by regulating CHOP and the KEAP1/NRF2 pathway

Abstract Objective UVB phototherapy is an important method for the treatment of psoriasis, but the specific mechanism is unclear. KLHDC7B is a Kelch domain-containing protein that has been widely noted involving in multiple important cellular processes, but its expression and function in psoriasis remain to be further elucidated. The objective of this study was to explore the levels of KLHDC7B in psoriasis lesions and psoriasis keratinocytes with UVB irradiation. In addition, this study aimed to investigate whether KLHDC7B participates in the UVB treatment in patients with psoriasis. Methods We used quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blotting to determine the levels of KLHDC7B. QRT-PCR and ELISA were used to detect the secretion levels of IL-1β, CCL20 and CXCL10. Cell apoptosis was analysed by flow cytometric method. QRT-PCR and Western blotting were used to detect the expression of CHOP and KEAP1/NRF2 pathway. The results were statistically analysed by t-test. Results Our study showed a high expression of KLHDC7B in psoriasis lesions and keratinocytes stimulated with M5 for the psoriasis model. After UVB treatment, KLHDC7B was further increased. Knockdown of KLHDC7B reversed UVB-induced apoptosis and levels of IL-1β, CCL20 and CXCL10. Overexpression of KLHDC7B can improve the endoplasmic reticulum stress marker protein CHOP expression and NRF2 level. KLHDC7B could induce CHOP-mediated apoptosis and activate the KEAP1/NRF2 pathway to alleviate inflammation. In addition, we found that UVB promoted KLHDC7B expression through the nearby LncRNA called LncKLHDC7B-2. Conclusion KLHDC7B may act as a disease suppressor and play a key role in UVB treatment for psoriasis, which may provide a new target for treatment.

Stachys byzantina K. Koch in the Treatment of Skin Inflammation: A Comprehensive Evaluation of Its Therapeutic Properties.

Stachys byzantina is a plant widely cultivated for food and medicinal purposes. Stachys species have been reported as anti-inflammatory, antibacterial, anxiolytic, and antinephritic agents. This study aimed to evaluate the anti-inflammatory potential of the ethanolic extract (EE) from the aerial parts of S. byzantina and its most promising fraction in models of acute and chronic inflammation, including a psoriasis-like mouse model. The EE was fractionated into hexane (HF), dichloromethane (DF), ethyl acetate (AF), and hydroalcoholic (HD) fractions. Screening for anti-inflammatory activity based on nitric oxide inhibition (IC50 μg/mL: HF 24.29 ± 5.87, EE 176.45 ± 18.65), hydroxyl radical scavenging (HF 3.89 ± 0.61, EE 6.38 ± 2.25), β-carotene/linoleic acid assay (HF 10.13 ± 3.81, EE 25.64 ± 2.12), and ORAC identified HF as the most active fraction. Topical application of HF effectively reduced croton oil- and phenol-induced ear edema in mice, with no statistical difference to the reference drugs. A formulation containing HF showed significant activity in the imiquimod-induced psoriasis model, reducing pro-inflammatory cytokines and nitric oxide production in macrophages, with no cytotoxicity to skin cells. Phytochemical analysis of HF revealed the presence of terpenes, steroids (491.68 ± 4.75 mg/g), phenols (34.30 ± 4.96 mg/g), flavonoids (151.77 ± 6.66 mg/g), and α-tocopherol, which was identified and quantified by HPLC-UV analysis (10.56 ± 0.97 mg/g of HF). These findings highlight the therapeutic potential of S. byzantina for skin inflammation, particularly contact dermatitis and psoriasis, encouraging further studies, including in human volunteers.

Lifitegrast, a Lymphocyte Function-Associated Antigen-1 Antagonist Demonstrates Beneficial Effect in Psoriasis.

Lifitegrast is a lymphocyte function-associated antigen-1 (LFA-1) antagonist, which is approved for treatment of dry eye disease. In this work we explored the effect of lifitegrast in imiquimod induced psoriasis model in mice. Lifitegrast (5% solution) was tested in imiquimod-induced psoriasis model in C57 mice. Lifitegrast was topically administered twice a day to the psoriatic skin for 6 days and epidermal skin thickness, psoriasis area and severity index (PASI) score and inflammation markers were assessed. Lifitegrast inhibited the imiquimod-induced increase in the epidermal thickness, histopathological changes and PASI score. This decrease in psoriasis inflammation was accompanied by decrease in TNF-α, IL-6, IL-22 and IL-17/IL-23 axis gene expression in the skin, and the effect is comparable to the oral cyclosporine A(5 mg/kg, twice a day) treatment. Lifitegrast demonstrated significant anti-inflammatory activity, mainly through reduction in cytokine gene expression related to psoriasis and decreased the severity of psoriasis in vivo. The significant effect shown by this LFA-1 and ICAM-1 antagonist indicates a novel topical treatment for psoriasis.

071 High-Fat Diet Promotes Chronicity of Skin Inflammation and IL-10 Resistance in a Murine Delayed-Type Hypersensitivity Reaction Model of Psoriasis

071 High-Fat Diet Promotes Chronicity of Skin Inflammation and IL-10 Resistance in a Murine Delayed-Type Hypersensitivity Reaction Model of Psoriasis

EE563 Considerations for Health Economic Modelling in a Crowded Treatment Landscape: Lessons From Recent Models for Psoriasis, Psoriatic Arthritis, and Ulcerative Colitis

EE563 Considerations for Health Economic Modelling in a Crowded Treatment Landscape: Lessons From Recent Models for Psoriasis, Psoriatic Arthritis, and Ulcerative Colitis

IWR-1 attenuates the promotional effect of IL-36γ in a mouse model of psoriasis

BackgroundPsoriasis is a chronic inflammatory skin disease. The Wnt/β-catenin signaling pathway is essential for the regulation of adult stem cells, homeostasis, and tissue regeneration; however, the relationship between this pathway and interleukin (IL)-36γ in the pathogenesis of psoriasis remains unclear.MethodsIn this study, psoriasiform model mice were established using imiquimod (IMQ) induction. Hematoxylin and eosin (H&E) staining was used to evaluate pathological morphologies, while immunohistochemistry was used to verify the expression patterns of β-catenin and the inflammatory factors IL-6, IL-17 A, and interferon (IFN)-γ.ResultsIL-36γ treatment increased psoriasis area and severity index scores, and enhanced proliferation of keratinocytes in IMQ-induced psoriatic mice. The effects of IL-36γ on the severity of psoriasiform lesions and epidermal hyperplasia were partly inhibited by IWR-1, which is an inhibitor of the Wnt/β-catenin signaling pathway. Furthermore, the levels of proinflammatory cytokines and molecules involved in the Wnt/β-catenin signaling pathway in psoriatic mouse skin, including IL-6, IL-17 A, IFN-γ, β-catenin, and Dickkopf-1 (DKK1), were upregulated by treatment with IL-36γ. Consistently, the effects of IL-36γ on the inflammatory response and the Wnt/β-catenin signaling pathway were alleviated by IWR-1.ConclusionsTaken together, our findings suggested that inhibition of the Wnt/β-catenin signaling pathway may be useful in the alleviation of IL-36γ-induced psoriasis-like lesions.

TOP2A Promotes Proliferation, Migration, and Inflammatory Response in M5-Treated Keratinocytes by Binding CTBP1 to Activate Wnt/β-Catenin Signaling.

Psoriasis is a chronic cutaneous disease, affecting a significant portion of the global population. Topoisomerase II alpha (TOP2A) is upregulated in psoriasis samples, but the precise molecular mechanism remains unclear. We aimed to clarify the biological contribution of TOP2A in psoriasis progression. An in vitro psoriasis model was established on M5-induced keratinocytes (HaCaT cells) to simulate the psoriasis-like alterations. Following TOP2A knockdown without or with c terminal binding protein 1 (CTBP1) overexpression, CCK-8 and EDU staining were employed to analyze the viability and proliferation of HaCaT cells under M5 conditions. The capacities of HaCaT cell migration and invasion were examined with wound healing- and transwell assays. RT-qPCR and immunoblotting were adopted for evaluation of the inflammation and differentiation of M5-stimualted HaCaT cells. Additionally, the binding between TOP2A and CTBP1 was predicated using bioinformatics tools and detected by Co-IP. Finally, the expression of proteins in Wnt/β-catenin signaling was analyzed with the application of immunoblotting. Results suggested that TOP2A was upregulated in psoriasis skin lesions and M5-induced HaCaT cells. Interference with TOP2A attenuated the proliferation, migration, invasion, and inflammatory response in M5-treated HaCaT cells. In particular, TOP2A bound to CTBP1 and upregulated CTBP1 expression in HaCaT cells. Remarkably, CTBP1 upregulation blocked the impacts of TOP2A depletion on the biological behaviors of M5-treated HaCaT cells. Besides, TOP2A deficiency upregulated DKK1 expression as well as downregulated Wnt1, β-catenin, and c-Myc expression in HaCaT cells exposed to M5, which was restored by further CTBP1 overexpression. In summary, TOP2A binds CTBP1 to activate Wnt/β-catenin signaling, thereby promoting the progression of psoriasis.

PVEMLPTS: design of an efficient psoriasis and vitiligo detection model through enhanced machine learning and personalized treatment strategies

PVEMLPTS: design of an efficient psoriasis and vitiligo detection model through enhanced machine learning and personalized treatment strategies

A polygenic risk score model for psoriasis based on the protein interactions of psoriasis susceptibility loci.

Polygenic Risk Scores (PRS) are an emerging tool for predicting an individual's genetic risk to a complex trait. Several methods have been proposed to construct and calculate these scores. Here, we develop a biologically driven PRS using the UK BioBank cohort through validated protein interactions (PPI) and network construction for psoriasis, incorporating variants mapped to the interacting genes of 14 psoriasis susceptibility (PSORS) loci, as identified from previous genetic linkage studies. We constructed the PPI network via the implementation of two major meta-databases of protein interactions, and identified variants mapped to the identified PSORS-interacting genes. We selected only European unrelated participants including individuals with psoriasis and randomly selected healthy controls using an at least 1:4 ratio to maximize statistical power. We next compared our PPI-PRS model to (i) clinical risk models and (ii) conventional PRS calculations through p-value thresholding. Our PPI-PRS model provides comparable results to both clinical risk models and conventional approaches, despite the incorporation of a limited number of variants which have not necessarily reached genome-wide significance (GWS). Exclusion of variants mapped to the HLA-C locus, an established risk locus for psoriasis resulted in highly similar associations compared to our primary model, indicating the contribution of the genetic variability mapped to non-GWS variants in PRS computations. Our findings support the implementation of biologically driven approaches in PRS calculations in psoriasis, highlighting their potential clinical utility in risk assessment and treatment management.