Pathology Of Psoriasis Research Articles

LGR4 Deficiency Aggravates Skin Inflammation and Epidermal Hyperplasia in Imiquimod-Induced Psoriasis.

Psoriasis is a chronic inflammatory skin disease characterised by inflammatory cell infiltration, keratinocyte hyperproliferation and increased neovascularization. Despite extensive research, the precise mechanisms underlying psoriasis pathology and treatment strategies remain unclear because of a complex aetiology and disease progression. Hence, in this study, we aimed to identify potential therapeutic targets for psoriasis and explore their effects on disease progression. We observed that G protein-coupled receptor LGR4 attenuates psoriasis progression. Bioinformatics analysis of publicly available clinical data revealed lower LGR4 expression in the skin lesions of patients with psoriasis than in their non-lesioned skin. Both invitro (HaCaT cell) and invivo (mouse) models confirmed this phenomenon. The Lgr4-knockout mouse model further confirmed that LGR4 plays a positive role in psoriasis progression. Specifically, Lgr4 knockout promoted the secretion of inflammatory factors, accumulation of local immunocyte infiltration in skin lesions, and keratinocyte proliferation. In conclusion, we demonstrated that LGR4 is critical to limiting psoriasis progression, suggesting that it is a viable target for the clinical management of this skin condition.

Pre-treatment plasma retinol binding protein 4 level and its change after treatments predict systemic treatment response in psoriasis patients

BackgroundRetinol binding protein 4 (RBP4) is a mediator of inflammation and related to skin lesion formation, which suggests its engagement in psoriasis pathology and progression. This study intended to explore the change in RBP4 after systemic treatments, and its ability to predict treatment response in psoriasis patients.MethodsThis prospective study enrolled 85 psoriasis patients and 20 healthy subjects. Plasma RBP4 was detected by enzyme-linked immunosorbent assay at baseline and 12th week (W12) after systemic treatments in psoriasis patients, as well as after enrollment in healthy subjects. Psoriasis Area and Severity Index (PASI) 75 and PASI 90 were evaluated at W12 in psoriasis patients.ResultsRBP4 at baseline was higher in psoriasis patients than in healthy subjects [median (interquartile range): 13.39 (9.71–22.92) versus 9.59 (6.57–13.72) µg/mL] (P = 0.003). In psoriasis patients, 50 (58.8%) patients achieved PASI 75 at W12, and 25 (29.4%) patients achieved PASI 90 at W12. RBP4 was decreased at W12 compared to its level at baseline (P < 0.001). Lower RBP4 at baseline predicted achieving PASI 75 at W12 (P = 0.038). Greater RBP4 change (baseline-W12) precited achieving PASI 75 (P = 0.036) and PASI 90 (P = 0.045) at W12. Receiver operating characteristic curves suggested that after adjustment for all clinical features, RBP4 at baseline and RBP4 change (baseline-W12) had an acceptable ability to predict PASI 75 and PASI 90 at W12 with all area under curve values > 0.7.ConclusionPlasma RBP4 is decreased after systemic treatments, and its low baseline level and greater decline after treatments predict good treatment response in psoriasis patients.

The role and therapeutic strategies for tissue-resident memory T cells, central memory T cells, and effector memory T cells in psoriasis.

Psoriasis is a skin disease that is inflammatory and persistent, causing a high rate of recurrence, poor quality of life, and significant socioeconomic burden. Its main pathological manifestations are abnormal activation and infiltration of T cells and excessive proliferation of keratinocytes (KCs). The great majority of patients with psoriasis will relapse after remission. It usually lasts a lifetime and necessitates long-term treatment strategies. During periods of activity and remission, one of the main cell types in psoriasis is memory T cells, which include tissue-resident memory T (TRM) cells, central memory T (TCM) cells, and effector memory T (TEM) cells. They work by releasing inflammatory factors, cytotoxic particles, or altering cell subpopulations, leading to increased inflammation or recurrence. This review summarizes the role of memory T cells in the pathology and treatment of psoriasis, with a view to potential novel therapies and therapeutic targets.

Efficacy and Safety of Orally Administered East Asian Herbal Medicine Combined with Narrowband Ultraviolet B against Psoriasis: A Bayesian Network Meta-Analysis and Network Analysis.

Psoriasis is a chronic, immune-mediated inflammatory skin disease with many complications and a poor prognosis that imposes a significant burden on individuals and society. Narrowband ultraviolet B (NB-UVB) represents a cost-effective non-drug therapeutic intervention for psoriasis. East Asian herbal medicine (EAHM) is currently being investigated for its potential as a safe and effective psoriasis treatment. Consequently, it has the potential to be employed as a combination therapy with NB-UVB. The objective was to ascertain the efficacy and safety of the EAHM with NB-UVB combination therapy and to identify important drugs for further research. In this study, randomized controlled trials (RCTs) were retrieved from ten databases in Korea, China, and Japan. All statistical analyses were conducted using R software version 4.3.0. The primary outcomes were the Psoriasis Area and Severity Index (PASI) and the incidence rate of adverse events (AEs), while the secondary outcomes were hematologic markers and the Dermatology Life Quality Index (DLQI), which reflect the immune-mediated inflammatory pathology of psoriasis. The analysis of 40 RCTs, including 3521 participants, demonstrated that EAHM with NB-UVB combination therapy exhibited a statistically significant superiority over NB-UVB monotherapy with respect to primary and secondary outcomes. The Bayesian network meta-analysis revealed that Investigator Presciption 3 and Ziyin Liangxue Decoction exhibited a consistent relative advantage with respect to each PASI-based efficacy metric. The network analysis estimated the potential influence ranking for all individual herbs according to PageRank centrality. The findings of this study suggest that EAHMs co-administered with NB-UVB may provide additional efficacy and safety-related benefits for patients with psoriasis. However, the quality of evidence is still low, and further high-quality trials are needed to reach more definitive conclusions.

An integrated bioinformatics approach for unravelling the molecular insights into psoriasis pathology and therapeutics

Psoriasis is a chronic relapsing inflammatory disease of the skin that affects almost 2–3 % population worldwide. The current treatment strategies include palliative therapeutics targeting the inflammatory pathways that do not completely cure the lesioned skin. The molecular cues in the hyper-proliferative and aberrantly differentiated keratinocytes of the psoriatic lesioned skin remain unknown. Through an integrative in-silico approach, we have analyzed human psoriatic skin samples from 3 RNA-Seq and 3 microarray datasets to identify 340 differentially expressed genes (DEGs). Further, these DEGs were analyzed using gene ontology enrichment, KEGG pathways, and protein-protein interaction networks for their role in disease pathology and the identification of hub genes. The expression of the hub genes was validated in a preclinical murine model of psoriasiform dermatitis. Finally, the ten hub genes were assessed for their drugability, which revealed 74 drugs targeting 7 hub genes (CCNA2, TOP2A, BIRC5, RRM2, CDK1, AURKA, and CCNB1) that can be repurposed for psoriasis treatment. This study provides an understanding of psoriasis pathophysiology and suggests key molecular biomarkers as therapeutic targets for effective mitigation of the disease.

Blood MALT1 expression could help predict treatment outcomes in psoriasis patients, especially in those receiving biologics.

Mucosa-associated lymphoid tissue 1 (MALT1) modulates T helper cell differentiation, pro-inflammatory cytokine production, and epidermal hyperplasia to participate in the pathology of psoriasis. This study aimed to explore the correlation of blood MALT1 with treatment outcomes in psoriasis patients. MALT1 was detected in peripheral blood mononuclear cells by reverse transcription-quantitative polymerase chain reaction in 210 psoriasis patients before starting or converting to a new therapy, 50 disease controls, and 50 healthy controls. The psoriasis area severity index (PASI) score was evaluated at month (M)1, M3, and M6 in psoriasis patients. MALT1 was increased in psoriasis patients versus disease controls and healthy controls (both p < .001); and positively related to body mass index (p = .019) and PASI score (p < .001) in psoriasis patients. PASI75 rate at M1, M3, and M6 was 22.9%, 46.2%, and 71.0%, respectively; while PASI90 rate at M1, M3, and M6 was 3.8%, 29.0%, and 50.5%, respectively, in psoriasis patients. PASI75/90 rates at M1, M3, and M6 were increased in psoriasis patients receiving biologics versus those without (all p < .05). Pretreatment MALT1 was higher in psoriasis patients who achieved PASI75 (p = .001) and PASI90 (p < .001) at M6 compared to those who did not achieve that. Subgroup analyses discovered that pretreatment MALT1 had a stronger ability to predict PASI75 and 90 realizations in psoriasis patients receiving biologics (area under the curve [AUC]: 0.723 and 0.808) versus those without (AUC: 0.594 and 0.675). Blood MALT1 measurement may assist in predicting outcomes in psoriasis patients, especially in those receiving biologics.

Brilaroxazine lipogel displays antipsoriatic activity in imiquimod-induced mouse model.

Dopamine (D) and serotonin (5-HT) pathways contribute to psoriasis pathobiology. Disruptions incite increased inflammatory mediators, keratinocyte activation and deterioration, and worsening symptoms. Brilaroxazine (RP5063), which displays potent high binding affinity to D2/3/4 and 5-HT1A/2A/2B/7 receptors and a moderate affinity to serotonin transporter (SERT), may affect the underlying psoriasis pathology. An imiquimod-induced psoriatic mouse model (BALB/c) evaluated brilaroxazine's activity in a topical liposomal-aqueous gel (Lipogel) formulation. Two of the three groups (n=6 per) underwent induction with 5% imiquimod, and one group received topical brilaroxazine Lipogel (Days 1-11). Assessments included (1) Psoriasis Area and Severity Index (PASI) scores (Days 1-12), skin histology for Baker score based on H&E stained tissue (Day 12), and serum blood collection for serum cytokine analysis (Day 12). One-way ANOVA followed by post hoc Dunnett's t-test evaluated significance (p<0.05). Imiquimod-induced animal Baker scores were higher versus Sham non-induced control's results (p<0.001). Brilaroxazine Lipogel had significantly (p=0.003) lower Baker scores versus the induced Psoriasis group. Brilaroxazine PASI scores were lower (p=0.03) versus the induced Psoriasis group (Days3-12), with the greatest effect in the last 3 days. The induced Psoriasis group showed higher Ki-67 and TGF-β levels versus non-induced Sham controls (p=0.001). The brilaroxazine Lipogel group displayed lower levels of these cytokines versus the induced Psoriasis group, Ki-67 (p=0.001) and TGF-β (p=0.008), and no difference in TNF-α levels versus Sham non-induced controls. Brilaroxazine Lipogel displayed significant activity in imiquimod-induced psoriatic animals, offering a novel therapeutic strategy.

Keratinocyte proline-rich protein modulates immune and epidermal response in imiquimod-induced psoriatic skin inflammation.

Psoriasis is a persistent inflammatory skin disease thought to arise as a result of the infiltration of inflammatory cells and activation of keratinocytes. Recent advances in basic research and clinical experience revealed that the interleukin (IL)-23/IL-17 axis has been identified as a major immune pathway in psoriasis. However, it remains unclear how keratinocyte factors contribute to the pathology of psoriasis. Keratinocyte proline-rich protein (KPRP) is a proline-rich insoluble protein, which is present in the epidermis and is likely to be involved in the skin barrier function. Here, to investigate the potential roles of KPRP in psoriatic skin inflammation, Kprp-modified mice were applied in the imiquimod (IMQ)-induced skin inflammation model, which develops psoriasis-like epidermal hyperplasia and cutaneous inflammation features. Then, heterozygous knockout (Kprp+/- ) but not homozygous knockout (Kprp-/- ) mice displayed attenuated skin erythema compared to control wild-type mice. In addition, RNA sequencing, quantitative PCR and/or histological analysis detected changes in the expression of several molecules related to psoriatic inflammation or keratinocyte differentiation in Kprp+/- mice, but not Kprp-/- mice. Further analysis exhibited reduced IL-17-producing γδlow T cells and amplified epidermal hyperplasia in Kprp+/- mice, which were implied to be related to decreased expression of β-defensins and increased expression of LPAR1 (Lysophosphatidic acid receptor 1), respectively. Thus, our results imply that KPRP has the potential as a therapeutic target in psoriatic skin inflammation.

Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9

ObjectiveTo explore whether the ethanol extract of Herpetospermum caudigerum Wall (EHC), a Xizang medicinal plant traditionally used for treating liver diseases, can improve imiquimod-induced psoriasis-like skin inflammation. MethodsImmunohistochemistry and immunofluorescence staining were used to determine the effects of topical EHC use in vivo on the skin pathology of imiquimod-induced psoriasis in mice. The protein levels of interferon-γ (IFN-γ), tumor necrosis factor-α (TNF-α), and interleukin-17A (IL-17A) in mouse skin samples were examined using immunohistochemical staining. In vitro, IFN-γ-induced HaCaT cells with or without EHC treatment were used to evaluate the expression of keratinocyte-derived intercellular cell adhesion molecule-1 (ICAM-1) and chemokine CXC ligand 9 (CXCL9) using Western blotting and reverse transcription-quantitative polymerase chain reaction. The protein synthesis inhibitor cycloheximide and proteasome inhibitor MG132 were utilized to validate the EHC-mediated mechanism underlying degradation of ICAM-1 and CXCL9. ResultsEHC improved inflammation in the imiquimod-induced psoriasis mouse model and reduced the levels of IFN-γ, TNF-α, and IL-17A in psoriatic lesions. Treatment with EHC also suppressed ICAM-1 and CXCL9 in epidermal keratinocytes. Further mechanistic studies revealed that EHC suppressed keratinocyte-derived ICAM-1 and CXCL9 by promoting ubiquitin–proteasome-mediated protein degradation rather than transcriptional repression. Seven primary compounds including ehletianol C, dehydrodiconiferyl alcohol, herpetrione, herpetin, herpetotriol, herpetetrone and herpetetrol were identified from the EHC using ultra-performance liquid chromatography-quadrupole-time of flight-mass spectrometry. ConclusionTopical application of EHC ameliorates psoriasis-like skin symptoms and improves the inflammation at the lesion sites.Please cite this article as: Zhong Y, Zhang BW, Li JT, Zeng X, Pei JX, Zhang YM, Yang YX, Li FL, Deng Y, Zhao Q. Ethanol extract of Herpetospermum caudigerum Wall ameliorates psoriasis-like skin inflammation and promotes degradation of keratinocyte-derived ICAM-1 and CXCL9. J Integr Med. 2023; Epub ahead of print.

Natural alternatives targeting psoriasis pathology and key signaling pathways: a focus on phytochemicals

Natural alternatives targeting psoriasis pathology and key signaling pathways: a focus on phytochemicals

Discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists with anti-psoriasis activity in a mouse model

Aryl hydrocarbon receptor (AHR) is a ligand dependent transcription factor and participates in the regulation of the immune balance of Th17/22 and Treg cells. It has been found to be widely expressed in the skin, and involved in the pathology of psoriasis. Therefore, AHR is thought as a potential intervention target for psoriasis. Here, we report the discovery of 5-((1H-indazol-3-yl) methylene)-2-thioxoimidazolidin-4-one derivatives as a new class of AHR agonists. Structure-activity relationship analyses led to the identification of the most active compound, 5- ((1H-indazol-3-yl)methylene) -3- (prop-2-yn-1-yl) -2-thiooimidazolidin-4-one (24e), which exhibited an EC50 value of 0.015 µM against AHR. Mechanism of action studies showed that 24e regulated the expression of CYP1A1 by activating the AHR pathway. Topical administration of 24e substantially alleviated imiquimod (IMQ)-induced psoriasis-like skin lesion. Overall, compound 24e could be a good lead compound for drug discovery against psoriasis, and hence deserving further in-depth studies.

Kynurenine Pathway in Psoriasis-a Promising Link?

Psoriasis is a common dermatosis which affects the patient's skin and general well-being because of its link to diseases such as depression, kidney disease and metabolic syndrome. Pathogenesis remains unknown; however, genetic, environmental and immunological factors seem to play a role in the development of the disease. Due to a lack of complete understanding of the psoriasis pathology, effective treatment is yet to be developed. The kynurenine pathway is one of the ways amino acid tryptophan is metabolised. In comorbidities typical for psoriasis such as chronic kidney disease, depression and atherosclerotic alterations in the activation of the kynurenine pathway were observed, which were mainly characterised by higher activity compared to that in healthy individuals. However, the kynurenine pathway has not been thoroughly studied among patients with psoriasis even though increased levels of L-kynurenine, one of the enzymes in the kynurenine pathway, were found in psoriatic skin lesions. Given the unknown pathogenesis of the disease, this finding seems to be a potential new field of study and shows a possible link between psoriasis and its comorbidities that could also lead to novel effective treatment for this chronic condition.

Pathology and Treatment of Psoriasis Using Nanoformulations

Psoriasis (PSO) is an inflammatory skin condition that causes a variety of diseases and significantly decreases the life characteristics of patients, and substantially diminishes patients’ quality of life. PSO usually impairs the skin and is linked to various disorders. Inflammation pathology does not only damage psoriatic skin; it shows how PSO impinges other body parts. Many variables interact with one another and can impact the etiology of psoriasis directly or indirectly. PSO has an effect on approximately 2% of the world’s population, and significant progress has been made in comprehending and treating the alternative PSO by novel drug delivery systems. Topical, systemic, biological, biomaterials, and phototherapy are some of the useful therapies for PSO. Nonetheless, topical treatments remain the gold standard for treating moderate PSO. The applicability of several nanocarrier systems, such as lipid nanoparticles, metallic nanoparticles, and certain phytocompounds, has been briefly explored. The present review focuses mainly on traditional therapeutic strategies as well as on breakthroughs in nanoformulations and drug delivery methods for several anti-psoriatic drugs.

IL-23/IL-17 immune axis mediates the imiquimod-induced psoriatic inflammation by activating ACT1/TRAF6/TAK1/NF-κB pathway in macrophages and keratinocytes.

The interleukin-23 (IL-23)/IL-17 immune axis has been linked to the pathology of psoriasis, but how this axis contributes to skin inflammation in this disease remains unclear. We measured inflammatory cytokines associated with the IL-23/IL-17 immune axis in the serum of patients with psoriasis using enzyme-linked immunosorbent assays. Psoriasis was induced in male C57BL/6J mice using imiquimod (IMQ) cream, and animals received intraperitoneal injections of recombinant mouse anti-IL-23A or anti-IL-17A antibodies for 7 days. The potential effects of the IL-23/IL-17 immune axis on skin inflammation were assessed based on pathology scoring, hematoxylin-eosin staining of skin samples, and quantitation of inflammatory cytokines. Western blotting was used to evaluate levels of the following factors in skin: ACT1, TRAF6, TAK1, NF-κB, and pNF-κB. The serum of psoriasis patients showed elevated levels of several cytokines involved in the IL-23/IL-17 immune axis: IL-2, IL-4, IL-8, IL-12, IL-17, IL-22, IL-23, and interferon-γ. Levels of IL-23p19 and IL-17 were increased in serum and skin of IMQ-treated mice, while ACT1, TRAF6, TAK1, NF-κB, and pNF-κB were upregulated in the skin. A large proportion of NF-κB p65 localized in nucleus of involucrin+ cells in the epidermis and in F4/80+ cells of the dermis of psoriatic lesional skin. Treating these animals with anti-IL-23 or anti-IL-17 antibodies improved pathological score and immune imbalance, mitigated skin inflammation and downregulated ACT1, TRAF6, TAK1, NF-κB, and pNF-κB in skin. Our results suggest that skin inflammation mediated by the IL-23/IL-17 immune axis in psoriasis involves activation of the ACT1/TRAF6/TAK1/NF-κB pathway in keratinocytes and macrophage.

Metabolic rewiring in keratinocytes by miR‐31‐5p identifies therapeutic intervention for psoriasis

Besides genetic alterations, the cellular environment also determines disease onset and progression. When different cell types contribute to disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. Hsa‐microRNA‐31‐5p (miR‐31) is highly expressed in keratinocytes of psoriatic skin, and we show that expression in keratinocytes is induced by limited glucose availability and enables increased survival under limiting glucose conditions by increasing glutamine metabolism. In addition, miR‐31 expression results in not only secretion of specific metabolites (aspartate and glutamate) but also secretion of immunomodulatory factors. We show that this miR‐31‐induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibitors of miR31‐induced metabolic rewiring and metabolic crosstalk with immune cells alleviate psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

Influence of aldo–keto reductase 1C3 polymorphisms in early-onset female psoriasis patients

The principal pathology of psoriasis is impaired skin barrier function, epidermal thickening, and granular layer loss. Exposure to extrinsic factors such as tobacco smoke and air pollutants is associated with the development of psoriasis. Aryl hydrocarbon receptors (AHRs) are activated by extrinsic factors associated with the development of psoriasis and act as transcriptional regulators. Expression of aldo–keto reductase (AKR) 1C3 in the epidermal spinous layer regulates epidermal keratinocyte differentiation via the AHR signaling pathway. We investigated whether single nucleotide polymorphisms (SNPs) in AKR1C3 are associated with the pathogenesis of psoriasis. The proportions of rs12529 G/C, C/C variants, and rs12387 A/A, A/G variants were twofold higher in Japanese psoriasis patients (n = 231) compared with a Japanese healthy cohort. The SNPs were significantly more common than the majority variants in female patients with disease onset ≤ 22 years of age. Patients with rs12529 G > C and rs12387 A > G SNPs exhibited significantly lower AKR1C3 expression and higher expression of late differentiation markers. In conclusion, AKR1C3 downregulation caused by rs12529 G > C and rs12387 A > G SNPs in the epidermis induces abnormal early differentiation of keratinocytes and skin barrier dysfunction, which may contribute to the genetic pathogenesis of psoriasis in young females.

Topical Diacerein Decreases Skin and Splenic CD11c+ Dendritic Cells in Psoriasis

Psoriasis is an inflammatory skin disease characterized by increased neo-vascularization, keratinocyte hyperproliferation, a pro-inflammatory cytokine milieu and immune cell infiltration. Diacerein is an anti-inflammatory drug, modulating immune cell functions, including expression and production of cytokines, in different inflammatory conditions. Therefore, we hypothesized that topical diacerein has beneficial effects on the course of psoriasis. The current study aimed to evaluate the effect of topical diacerein on imiquimod (IMQ)-induced psoriasis in C57BL/6 mice. Topical diacerein was observed to be safe without any adverse side effects in healthy or psoriatic animals. Our results demonstrated that diacerein significantly alleviated the psoriasiform-like skin inflammation over a 7-day period. Furthermore, diacerein significantly diminished the psoriasis-associated splenomegaly, indicating a systemic effect of the drug. Remarkably, we observed significantly reduced infiltration of CD11c+ dendritic cells (DCs) into the skin and spleen of psoriatic mice with diacerein treatment. As CD11c+ DCs play a pivotal role in psoriasis pathology, we consider diacerein to be a promising novel therapeutic candidate for psoriasis.

Peptide-Protected Gold Nanoclusters Efficiently Ameliorate Acute Contact Dermatitis and Psoriasis via Repressing the TNF-α/NF-κB/IL-17A Axis in Keratinocytes

Immune-mediated skin diseases have a high prevalence and seriously affect patients' quality of life. Gold compounds have been considered promising therapeutic agents in dermatology, but the high incidence of adverse reactions have limited their clinical application. There is a great need to develop more effective and less toxic gold-based drugs. Gold nanoclusters fabricated by using peptides (pep-AuNCs) have appeared as potential biomedical nanomaterials because of their excellent biocompatibility, ease of fabrication and unique physicochemical properties. Glutathione (GSH) is an endogenous tripeptide and has been used for lightening the skin color. Therefore, we fabricated a well-defined gold nanocluster with GSH as an example to explore the immunomodulatory effect of AuNCs on a TNF-α-treated human keratinocyte cell line (HaCaT) in vitro, the 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced irritant contact dermatitis (ICD) model and the oxazolone (OXA)-induced psoriatic model in vivo. The results indicated that topically applied AuNCs successfully attenuated the severity of ICD and psoriasis-like lesions. In vitro and in vivo, AuNCs effectively inhibited the abnormal activation of the NF-κB pathway and the consequent overexpression of proinflammatory cytokines in keratinocytes. In particular, the transactivation of IL-17A, the most important cytokine in psoriasis pathology, was effectively inhibited by AuNCs treatment. In addition, AuNCs did not show any obvious cytotoxicity in HaCaT cells at doses even up to 100 µM and did not induce any irritation in the healthy skin and major organs, which indicated their favorable biosafety. These results indicate that biocompatible pep-AuNCs might be a promising gold-based nanomedicine for the treatment of inflammatory skin diseases.

Targeting the transcription factor HES1 by L-menthol restores protein phosphatase 6 in keratinocytes in models of psoriasis

Protein Phosphatase 6 down-regulation in keratinocytes is a pivotal event that amplifies the inflammatory circuits in psoriasis, indicating that restoration of protein phosphatase 6 can be a rational strategy for psoriasis treatment. Through the phenotypic screen, we here identify L-menthol that ameliorates psoriasis-like skin inflammation by increasing protein phosphatase 6 in keratinocytes. Target identification approaches reveal an indispensable role for the transcription factor hairy and enhancer of split 1 in governing the protein phosphatase 6-upregulating function of L-menthol in keratinocytes. The transcription factor hairy and enhancer of split 1 is diminished in the epidermis of psoriasis patients and imiquimod-induced mouse model, while L-menthol upregulates the transcription factor hairy and enhancer of split 1 by preventing its proteasomal degradation. Mechanistically, the transcription factor hairy and enhancer of split 1 transcriptionally activates the expression of immunoglobulin-binding protein 1 which promotes protein phosphatase 6 expression and inhibits its ubiquitination. Collectively, we discover a therapeutic compound, L-menthol, for psoriasis, and uncover the dysfunctional the transcription factor hairy and enhancer of split 1- immunoglobulin-binding protein 1- protein phosphatase 6 axis that contributes to psoriasis pathology by using L-menthol as a probe.

Dissolvable hyaluronic acid microneedles loaded with β-Elemene for the treatment of psoriasis.

The pathology of psoriasis involves the over-proliferation of keratinocytes, exaggerated inflammation of keratinocytes, and infiltration of inflammatory cells such as macrophages (Mø), etc. The therapeutic outcomes of current treatment targeting one single pathological process are less than satisfactory. Based on their diverse biological activities, natural products offer a potential solution to this problem. In this study, we investigated the effects of β-Elemene (ELE) on both psoriatic keratinocytes and M1-type Mø (M1-Mø) in vitro. Hyaluronic acid (HA) microneedles loaded with ELE (HA-ELE-MN) were also fabricated and tested for the treatment of psoriasis in vivo using an imiquimod (IMQ)-induced psoriatic mice model. Our data suggest that ELE induces apoptosis and inhibits inflammation of psoriatic keratinocytes. In addition, ELE attenuates the expression of inflammatory cytokines secreted from M1-Mø, thus indirectly inhibiting the inflammation of keratinocytes. Furthermore, HA-ELE-MN has been found to significantly alleviate symptoms in an IMQ-induced psoriatic mice model by inducing keratinocytes apoptosis, suppressing keratinocytes proliferation, and inhibiting M1-Mø infiltration. Taken together, this study demonstrates that ELE can be used for the treatment of psoriasis by targeting both keratinocytes and M1-Mø, which provides a potential novel reagent for psoriasis treatment.