Excessive Proliferation Of Keratinocytes Research Articles

Downregulation of Ebp1Khib210 promotes keratinocyte proliferation through induction of TIF-IA-mediated rRNA synthesis.

Psoriasis is a prevalent chronic inflammatory dermatosis characterized by excessive proliferation of keratinocytes. Protein lysine 2-hydroxyisobutyrylation (Khib) is a newly identified post-translational modification that regulates various biological processes. Abnormal Khib modification has been closely associated with the development of autoimmune diseases. To investigate the abnormal Khib profile and its pathogenic role in psoriasis. We utilized liquid chromatography-tandem mass spectrometry to analyze Khib-modified proteins in the epidermis of psoriasis and healthy controls. Mutated cells and mice with downregulated Ebp1Khib210 were generated to investigate its functional effects in psoriasis. The omic analysis revealed dysregulation of Khib modification in psoriatic lesions, exhibiting a distinct profile compared to controls. We observed the downregulation of Ebp1Khib210 in psoriatic lesions and IMQ-induced psoriatic mice. Notably, the expression of Ebp1Khib210 was upregulated in psoriatic patients following effective treatment. Decreased Ebp1Khib210 enhanced keratinocyte viability, proliferation, and survival while inhibiting apoptosis in vitro. Additionally, Pa2g4K210A mice with downregulated Ebp1Khib210 exhibited more severe psoriatic lesions and enhanced keratinocyte proliferation. Moreover, we found that Ebp1K210A mutation increased the interaction between Ebp1 and nuclear Akt, thereby inhibiting MDM2-mediated TIF-IA ubiquitination, and resulting to increased rRNA synthesis and keratinocyte proliferation. The downregulation of Ebp1Khib210 was attributed to inflammation-induced increases in HDAC2 expression. Our findings demonstrate that downregulation of Ebp1Khib210 promotes keratinocyte proliferation through modulation of Akt signaling and TIF-IA-mediated rRNA synthesis. These insights into Khib modification provide a better understanding of the pathogenesis of psoriasis and suggest potential therapeutic targets.

Targeted siRNA Therapy for Psoriasis: Translating Preclinical Potential into Clinical Treatments.

Psoriasis is a chronic inflammatory skin disease characterized by the excessive proliferation of keratinocytes and heightened immune activation. Targeting pathogenic genes through small interfering RNA (siRNA) therapy represents a promising strategy for the treatment of psoriasis. This mini-review provides a comprehensive summary of siRNA research targeting the pathogenesis of psoriasis, covering aspects such as keratinocyte function, inflammatory cell roles, preclinical animal studies, and siRNA delivery mechanisms. It details recent advancements in RNA interference that modulate key factors including keratinocyte proliferation (Fibroblast Growth Factor Receptor 2, FGFR2), apoptosis (Interferon Alpha Inducible Protein 6, G1P3), differentiation (Grainyhead Like Transcription Factor 2, GRHL2), and angiogenesis (Vascular Endothelial Growth Factor, VEGF); immune cell infiltration and inflammation (Tumor Necrosis Factor-Alpha, TNF-α; Interleukin-17, IL-17); and signaling pathways (JAK-STAT, Nuclear Factor Kappa B, NF-κB) that govern immunopathology. Despite significant advances in siRNA-targeted treatments for psoriasis, several challenges persist. Continued scientific developments promise the creation of more effective and safer siRNA medications, potentially enhancing the quality of life for psoriasis patients and revolutionizing treatments for other diseases. This article focuses on the most recent research advancements in targeting the pathogenesis of psoriasis with siRNA and explores its future therapeutic prospects.

Interferon-Alpha Induces Psoriatic Inflammation in Mice by Phosphorylating FOXO3.

Psoriasis is a chronic, immune-mediated inflammatory skin disease characterized by epidermal thickening and inflammatory cell infiltration. Excessive proliferation of keratinocytes and resistance to apoptosis lead to thickening of the epidermis. Plasmacytoid dendritic cells are involved in the occurrence of psoriasis mainly by secreting interferon-alpha (IFN-α). IFN-α is a glycoprotein with antiviral, antitumor, and immunomodulatory effects, but its role in psoriasis remains unclear. In this investigation, a mild psoriatic phenotype was observed in mice upon topical application of IFN-α cream, and the inflammation was exacerbated when combined with imiquimod (IMQ). Immunohistochemical analyses demonstrated that IFN-α induces psoriatic inflammation in mice by stimulating phosphorylation of forkhead box O3, consistent with the involvement of this protein in cell proliferation, apoptosis, and inflammation. Our results suggested that topical IFN-α caused psoriatic inflammation and that the psoriatic inflammation was exacerbated by the combination of IFN-α and IMQ, possibly due to the dysfunction of forkhead box O3.

Gentiopicrin-Loaded Chitosan Nanoparticles as a Topical Agent for the Treatment of Psoriasis.

Psoriasis, a chronic inflammatory skin disease induced by various factors, including genetic factors, immune factors, environmental factors, and psychological factors, is characterized by thickening of the epidermis, excessive proliferation of keratinocytes, abnormal differentiation, and an excessive inflammatory response. Traditional treatments for psoriasis still face challenges because of limited curative effects, notable side effects, and a tendency for recurrence. In contrast, topical therapy provides a favorable option for psoriasis treatment because of its noninvasive and self-administered method. In this study, gentiopicrin (Gen) is encapsulated in the liposomes to form a nanodrug, and then chitosan is covered on the nanodrug to assemble the nanodrug delivery system (CS@Gen), which is used as a topical agent for treating psoriasis. Then M5 (a mixture of five pro-inflammatory cytokines, i.e., IL-17A, IL-22, IL-1α, oncostatin M, and TNF-α)-induced HacaT cells and imiquimod-induced psoriasis mouse models are established, whose results show that CS@Gen induces apoptosis and inhibits the proliferation and cell migration of psoriasis keratinocytes. Additionally, the application of CS@Gen cream can significantly reduce epidermal thickness, diminish skin scaling, and improve other related mechanisms in mice affected by psoriasis. Meanwhile, the prepared CS@Gen can significantly reduce the expression levels of IL-17a, Cxcl2, S100a, Mki67, and other related inflammatory factors, resulting in indirectly inhibiting the inflammation of keratinocytes. In summary, the present study provides an ideal loading for an anti-inflammatory and immunomodulatory drug delivery system for the treatment of psoriasis.

Role of co‑inhibitory molecules in the treatment of psoriasis (Review).

Psoriasis is a common chronic inflammatory skin disease characterized by abnormal activation and infiltration of T-cells and excessive proliferation of keratinocytes (KCs). Its pathogenesis is complex and frequently accompanied by the imbalance of T-cell subpopulations, contributing to its development and further exacerbation. Therefore, the immune system, especially T-cells, is mainly involved in the pathogenesis of psoriasis. While T-cell activation not only requires the first recognition of T-cell receptor and major histocompatibility complex peptide, co-stimulatory and co-inhibitory pathways are reported to promote or dampen T-cell responses through a variety of mechanisms. In recent years, immuno-related agents have been applied in the treatment of numerous clinical diseases, including psoriasis, and are starting to show promising and potential therapy prospects in autoimmune skin diseases. The present review outlined the role of co-inhibitory molecules in the pathogenesis of psoriasis and their application in the treatment of psoriasis.

Glycyl–tRNA Synthetase Induces Psoriasis-Like Skin by Facilitating Skin Inflammation and Vascular Endothelial Cell Angiogenesis

Psoriasis is characterized by excessive keratinocyte proliferation and immunocyte infiltration, but the underlying pathogenesis remains unclear. Aminoacyl-tRNA synthetases are universally expressed enzymes that catalyze the first step of protein synthesis. Glycyl-tRNA synthetase (GARS) is a member of the aminoacyl-tRNA synthetase family. In addition to its canonical function, we found that GARS was overexpressed in the serum and skin lesions of patients with psoriasis. Moreover, GARS was highly expressed in human skin keratinocytes, and GARS knockdown in keratinocytes suppressed cell proliferation and promoted apoptosis through NF-κB/MAPK signaling pathway. Moreover, intradermal injection of recombinant GARS protein caused skin thickening, angiogenesis, and IFN/TNF-driven skin inflammation. Intriguingly, the reported functional receptor for GARS, cadherin 6 (CDH6), was specifically expressed in vascular endothelial cells, and we found that keratinocyte-derived GARS promotes inflammation and angiogenesis of vascular endothelial cells through CDH6. In addition, intradermal injection of GARS aggravated the phenotype and angiogenesis in imiquimod-induced psoriasiform dermatitis models, whereas the psoriatic phenotype and angiogenesis were relieved after knockdown of GARS by adeno-associated virus. Taken together, the results of this study identify the critical role of GARS in the pathogenesis of psoriasis and suggest that blocking GARS may be a therapeutic approach for alleviating psoriasis.

Circular RNA sequencing identified circARNTL2 as a pathogenic factor in psoriasis by facilitating proliferation and cell cycle progression of keratinocytes

Psoriasis is a chronic recurrent skin disease, with excessive proliferation of keratinocytes. Recent studies indicated the pathogenic roles of circular RNA (circRNA) in psoriasis. Here, we screened the circRNA profiles from five psoriatic skin lesions and five normal skin tissues by circRNA sequencing and identified 1118 differentially expressed circRNAs (DECs) between psoriatic and normal groups. Among these DECs, high abundant circARNTL2 has been proven upregulated in psoriatic skin lesions by RT-qPCR assay. Then, the head-to-tail structure of circARNTL2 was validated by Sanger sequencing and RNase R digestion assay. Moreover, we determined cytoplastic location of circARNTL2 by RT-qPCR assay of nuclear/cytoplasmic RNA and FISH analysis. Further experiments demonstrated that silencing circARNTL2 expression could block cell proliferation and cell cycle progression of keratinocytes. Mechanistically, circARNTL2 can bind to and regulate Serpin B4 which also affects the proliferation of keratinocytes. These findings provide evidence for the role of circARNTL2 in psoriasis.

Zerumbone attenuates the excessive proliferation of keratinocytes in psoriasis mice through regulating NLRP3/NF-κB pathway.

Psoriasis is a common chronic disease, and existing treatment regimens often exhibit certain toxicities and side effects. Zerumbone (Zer) may possess therapeutic effect, and the objective of this study is to investigate the effect of Zer on psoriasis. A mouse model of psoriasis was established using imiquimod cream, and the role of Zer on the pathological alterations in psoriatic mouse skin was evaluated by psoriasis area and severity index (PASI) score; the effect of Zer on keratinocyte proliferation was evaluated via hematoxylin and eosin staining, Zen image analysis, and immunofluorescence; Immunohistochemistry and enzyme-linked immunoassay were used to evaluate the effect of Zer on tissue inflammatory responses, while malondialdehyde (MDA) and glutathione (GSH) levels were measured to elucidate the role of Zer in modulating oxidative stress; the signaling pathway regulated by Zer was evaluated by western blotting. The results demonstrated that Zer could alleviate the pathological manifestations of psoriasis, reduce PASI score, reduce skin pathological damage and epidermal hyperplasia, diminish the number of CD8+ T cells and cytokine expression levels, decrease the level of MDA and GSH and increase the expression of Nrf and HO-1. Zer was found to regulate the NLRP3/nuclear factor-kappa B (NF-κB) signaling pathway. In conclusion, Zer ameliorated the symptoms of psoriasis in mice, suppressed the keratinocyte hyperproliferation, and mitigates inflammation and oxidative stress in psoriatic skin tissue by regulating the NLRP3/NF-κB pathway.

Pathogenic role of S100 proteins in psoriasis.

Psoriasis is a chronic inflammatory skin disease. The histopathological features of psoriasis include excessive proliferation of keratinocytes and infiltration of immune cells. The S100 proteins are a group of EF-hand Ca2+-binding proteins, including S100A2, -A7, -A8/A9, -A12, -A15, which expression levels are markedly upregulated in psoriatic skin. These proteins exert numerous functions such as serving as intracellular Ca2+ sensors, transduction of Ca2+ signaling, response to extracellular stimuli, energy metabolism, and regulating cell proliferation and apoptosis. Evidence shows a crucial role of S100 proteins in the development and progress of inflammatory diseases, including psoriasis. S100 proteins can possibly be used as potential therapeutic target and diagnostic biomarkers. This review focuses on the pathogenic role of S100 proteins in psoriasis.

Study on the Key Genes and Molecular Mechanisms of IL-27 Promoting Keratinocytes Proliferation Based on Transcriptome Sequencing.

IL-27 involves psoriasis pathogenesis potentially by promoting excessive keratinocyte proliferation. However, the underlying mechanisms remain unclear. This study aims to explore the key genes and molecular mechanisms of IL-27-induced keratinocyte proliferation. Primary keratinocytes and immortalized human keratinocyte HaCaT cells were treated with different concentrations of IL-27 for 24 h and 48 h respectively. CCK-8 assay was used to detect cell viability and Western blot was used to detect the expression of CyclinE and CyclinB1. Primary keratinocytes and HaCaT cells were treated with IL-27, and their differentially expressed (DE) genes were obtained by transcriptome sequencing. Then Kyoto Encyclopedia of Genes and Genomes enrichment analysis was performed to predict related pathways, and the long non-coding RNA-microRNA-messenger RNA network and protein-protein interaction network were constructed to screen key genes. Biochemical experiments were performed to assess the content of glucose (Glu), lactic acid (LA), and ATP. Flow cytometry and Mito-Tracker Green staining were used to detect mitochondrial membrane potential and the number of mitochondria respectively. Western blot was performed to assess the expression of glucose transporter 1 (GLUT1), hexokinase 2 (HK2), lactate dehydrogenase A (LDHA), phosphoglycerate kinase 1 (PGK1), phosphorylated dynamin-related protein 1 (p-DRP1) (s637) and mitofusin 2 (MFN2). IL-27 concentration-dependently increased keratinocyte viability and the expression of CyclinE and CyclinB1. Bioinformatics analysis showed that the enriched pathways of DE genes were closely associated with cellular metabolism. miR-7-5p, EGFR, PRKCB, PLCB1 and CALM3 were key genes. IL-27 increased the content of LA, mitochondrial membrane potential, and the expression of GLUT1, HK2, LDHA, PGK1, p-DRP1 (s637), and MFN2, accompanied by decreased contents of Glu and ATP (P<0.001). IL-27 potentially promotes keratinocyte proliferation by enhancing glycolysis, mitochondrial function, and mitochondrial fusion. The findings of this study may be conducive to revealing the role of IL-27 in the pathogenesis of psoriasis.

Erianin-Loaded Photo-Responsive Dendrimer Mesoporous Silica Nanoparticles: Exploration of a Psoriasis Treatment Method.

Psoriasis is a chronic inflammatory skin disorder accompanied by excessive keratinocyte proliferation. Erianin (Eri) is an ideal drug candidate for inhibiting proliferation and inducing apoptosis in the treatment of psoriasis. However, Eri’s poor water solubility and low penetration activity across the skin hinder its application in local medicine. In this study, we developed a novel photo-responsive dendritic mesoporous silica nanoparticle-based carrier to deliver erianin, improved its bioavailability, and achieved sustained-release effects. Spiropyran (SP), 3-aminopropyltriethoxysilane (APTES), and perfluorodecyltriethoxysilane (PFDTES) were conjugated to the outer surface, which allowed Eri to be released in response to UV radiation. The physicochemical properties of photo-responsive dendritic mesoporous silica nanoparticles (Eri-DMSN@FSP) were characterized via multiple techniques, such as using a Fourier-transform infrared spectrometer, a high-resolution transmission electron microscope, and nuclear magnetic resonance (NMR) spectroscopy. The anti-proliferative properties and light-triggered release of erianin-loaded photo-responsive dendritic mesoporous silica nanoparticles were assessed via the MTT assay and a drug release study in vitro. Erianin-loaded photo-responsive dendritic mesoporous silica nanoparticles (UV) exhibit a significantly enhanced HaCat cell-inhibiting efficacy compared to other formulations, as demonstrated by their extremely low cell viability of 10.0% (concentration: 500 mg/mL), indicating their capability to release a drug that responds to UV radiation. The cellular uptake of photo-responsive dendritic mesoporous silica nanoparticles (DMSN@FSP) was observed via confocal laser scanning microscopy (CLSM). These experimental results show that Eri-DMSN@FSP could be effectively endocytosed into cells and respond to ultraviolet light to release Eri, achieving a more effective psoriasis treatment. Therefore, this drug delivery system may be a promising strategy for addressing the question of Eri’s delivery and psoriasis therapy.

Barrier function of the skin and the role of fat-soluble vitamins in the correction of its disorders

The main function of the skin is to protect the body from negative environmental influences. The physical barrier permeability is mainly represented by the stratum corneum; however, other layers of the epidermis and the dermis are its important components. The mechanical strength of the skin is provided by intercellular contacts in the epidermis and structural proteins of the dermis. The chemical-biological barrier includes lipids, acids, natural moisturizing factor and antimicrobial peptides. Mucosal immunity system creates a barrier against infection. The microflora of healthy skin counteracts its colonization by pathogens and is vital for its immune functions. Physiological processes in the skin are closely related. A violation in one of them often leads to the formation of a whole cascade of pathological reactions affecting all the links of its protection. Vitamins A, D and E are used to correct impaired barrier function of the skin. The most pronounced effect of vitamin A (retinol palmitate) is the proliferation of epidermal cells and synthesis of extracellular matrix structures of the dermis; vitamin D (cholecalciferol) regulation of differentiation and suppression of excessive proliferation of keratinocytes; vitamin E (tocopherol acetate) antioxidant effect. The combined use of these vitamins in the composition of RadevitActive ointment affects all the main elements of the protection of the epidermis and dermis: strengthens the mechanical strength of the stratum corneum and dermis, stabilizes chemical and physical protection, including prevents the penetration of foreign substances and microorganisms, reduces transepidermal loss of water and electrolytes, reduces the damaging effect of UV, increases antimicrobial and antioxidant protection.

Gene interaction analysis of psoriasis in Chinese Han population.

Background/aimsPsoriasis is a chronic immune‐mediated inflammatory skin disease characterized by excessive proliferation of keratinocytes. It has a strong genetic predisposition; gene‐gene interactions are important genetic models for common diseases. In this study, we explore pair‐wise interactions among SNPs contributing to psoriasis susceptibility.MethodsWe first performed gene interactions with exome‐sequencing, next, we analyzed gene interactions combining the exome sequencing data with the targeted sequencing data. After we sequenced HLA region, we analyzed gene interactions including HLA regions and non‐HLA regions.ResultsWe found interactions between HLA regions were significant. We observed significant interactions between HLA‐C*06:02 and rs118179173 (snp31443520; p = 8.21 × 10−20, OR = 0.22) and between HLA‐C*06:02 and HLA‐B:AA67 (p = 1.22 × 10−12, OR = 0.45).ConclusionThis study provides evidence that HLA is the most important susceptibility region on the risk of psoriasis and interactions that occur in this region are still significant.

Pinocembrin Reduces Keratinocyte Activation and Ameliorates Imiquimod-Induced Psoriasis-like Dermatitis in BALB/c Mice through the Heme Oxygenase-1/Signal Transducer and Activator of Transcription 3 Pathway.

Psoriasis is an autoimmune disease characterized by chronic skin inflammation and excessive keratinocyte proliferation. The itchy, scaly, and erythematous lesions present on psoriatic skin negatively affect patients' quality of life. Pinocembrin is a flavonoid present in propolis, fruits, and vegetables. It exerts neuroprotective effects and was used for treating ischemic stroke in a human clinical trial. However, the effects of pinocembrin on psoriasis have never been examined. In this study, we evaluated the effects of pinocembrin on human HaCaT keratinocytes and BALB/c mice with imiquimod- (IMQ-) induced psoriatic dermatitis. In interferon-γ- (IFN-γ-) activated HaCaT cells, pinocembrin reduced the expression of inflammatory cytokines, namely, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and keratinocyte proliferation markers, namely, keratin (K)16, K17, and Ki-67. The mechanism underlying these inhibitory effects involved the regulation of the heme oxygenase- (HO-) 1/signal transducer and activator of transcription (STAT) 3 pathway. In the IMQ-induced psoriatic dermatitis mouse model, the topical application of pinocembrin significantly ameliorated the Skin Psoriasis Area and Severity Index score, epidermal thickness, inflammation, hyperplasia, hyperkeratosis, and cluster of differentiation (CD) 4+ T-cell infiltration. Expression of the inflammatory cytokines and keratinocyte proliferation markers in dorsal skin was significantly decreased in the pinocembrin-treated group. Meanwhile, in lesional skin, the expression of HO-1 was upregulated, but that of phospho-STAT3 (pSTAT3) was downregulated. Collectively, our results indicated the therapeutic potential of pinocembrin. Additional studies are warranted to evaluate its clinical benefits in patients with psoriasis.

Kirenol inhibits TNF-α-induced proliferation and migration of HaCaT cells by regulating NF-κB pathway

Psoriasis is a common chronic, inflammatory skin disease possessing properties of inflammatory cell infiltration and excessive proliferation of keratinocytes, the occurrence and development of which remain fully elucidated. Therefore, the study was designed to determine the effects of kirenol (50, 100 and 200 μg/mL) on Cultured Human Keratinocytes (cells) (HaCaT) in vitro and reveal its molecular mechanism. The in vitro psoriasis model was established utilizing tumor necrosis factor-α (TNF-α)-stimulated HaCaT cells. Kirenol, a diterpenoid compound, was applied at different concentrations (50, 100 and 200 μg/mL) to HaCaT cells for 24 h. The Cell Counting Kit-8 (CCK-8) and thymidine monobromodeoxyuridine (BrdU) assays were used to assess cell viability and proliferation, followed by assessment of cell migration by Transwell assay. Subsequently, inflammatory cytokines were measured by enzyme-linked immunosorbent assay (ELISA), and Western blot assay was used to evaluate expressions of p65, p-p65, IκBα and p-IκBα. Activities of superoxide dismutase (SOD), catalase (CAT), glutathione (GSH) and malondialdehyde (MDA) contents were measured spectrophotometrically. The results demonstrated that TNF-α induced a significant increase in cell viability and inflammatory cytokines, including expressions of Interleukin (IL)-6, IL-8, IL-22 and IL-1β in HaCaT cells, which was dose-dependently inhibited by kirenol. Similarly, TNF-α-induced cell migration was also suppressed by kirenol treatment. Furthermore, TNF-α stimuli induced the upregulation of phosphorylation levels of p65 and IκBα as well as p-p65–p65 and p-IκBα–IκBα ratios, whereas kirenol significantly suppressed the activation of cellular nuclear factor-kappa B (NF-κB) signaling pathway. In addition, kirenol significantly decreased the level of MDA but increased the levels of SOD, CAT and GSH in a dose-dependent manner. These results proposed that kirenol could inhibit the proliferation, migration, expression of inflammatory factors, and oxidative stress in HaCaT cells via suppressing NF-κB signaling pathway.

Cudraxanthone D Ameliorates Psoriasis-like Skin Inflammation in an Imiquimod-Induced Mouse Model via Inhibiting the Inflammatory Signaling Pathways.

Psoriasis is a chronic inflammatory skin disease accompanied by excessive keratinocyte proliferation. Corticosteroids, vitamin D3 analogs, and calcineurin inhibitors, which are used to treat psoriasis, have diverse adverse effects, whereas natural products are popular due to their high efficiency and relatively low toxicity. The roots of the Cudrania tricuspidata (C. tricuspidata) are known to have diverse pharmacological effects, among which the anti-inflammatory effect is reported as a potential therapeutic agent in skin cells. Nevertheless, its effectiveness against skin diseases, especially psoriasis, is not fully elucidated. Here, we investigated the effect of cudraxanthone D (CD), extracted from the roots the C. tricuspidata Bureau, on psoriasis using an imiquimod (IMQ)-induced mouse model and the tumor necrosis factor (TNF)-α/interferon (IFN)-γ-activated keratinocytes. IMQ was topically applied to the back skin of C57BL/6 mice for seven consecutive days, and the mice were orally administered with CD. This resulted in reduced psoriatic characteristics, such as the skin thickness and Psoriasis Area Severity Index score, and the infiltration of neutrophils in IMQ-induced skin. CD inhibited the serum levels of TNF-α, immunoglobulin G2a, and myeloperoxidase, and the expression of Th1/Th17 cells in splenocytes. In TNF-α/IFN-γ-activated keratinocytes, CD reduced the expressions of CCL17, IL-1β, IL-6, and IL-8 by inhibiting the phosphorylation of STAT1 and the nuclear translocation of NF-kB. Taken together, these results suggest that CD could be a potential drug candidate for the treatment of psoriasis.

Cellular nanovesicles with bioorthogonal targeting enhance photodynamic/photothermal therapy in psoriasis

The interaction between over-proliferating keratinocytes and excessive activated immune cells contributes to the development and progression of psoriasis. Photodynamic therapy (PDT)/photothermal therapy (PTT) is a promising method to treat skin diseases due to their synergistic effect and low side effect. Cell membrane is an ideal cell-mediated drug delivery platform with inherent biocompatibility, but lacks of specific targeting properties to increase drug accumulation in the psoriatic site. Here, we develop a new PDT/PTT strategy to treat psoriasis, based on cell membrane functionalization by metabolic glycoengineering with unnatural sugars, which label cell membranes with chemical tags for subsequent targeting. In our study, in order to enhance the PDT/PTT effect, N3-labeled cell membrane-derived nanovesicles coated with IR-780 nanoparticals (N3-NV-INPs) are constructed, which can specifically recognize DBCO-modified psoriatic lesions through bioorthogonal click chemistry to achieve targeted PDT/PTT effect. The results showed that N3-NV-INPs could specifically target the psoriatic lesions, enhance the synergistic effect of PDT/PTT under the irradiation of near-infrared light, exhaust excessive proliferation of keratinocytes, regulate immunity, reduce the release of cytokines, such as IL-17, IL-22, TNF-α, improve epidermal hyperplasia, and effectively relieve the symptoms of psoriasis. Taken together, we constructed cellular nanovesicles based on an alternative artificial targeting strategy to enhance PDT/PTT effect in psoriasis, which shows great potential in clinical application. Statement of significanceThe major challenge in the treatment of psoriasis is how to effectively deliver drugs to the lesions to exhaust overproliferating keratinocytes and modulate immunity. A newly-developed cell membrane-coating technology combined with biorthogonal targeted delivery promotes more drug accumulation at the lesions of the disease. Incorporation of an effective photosensitizer into the lesions of psoriasis site results in exert PDT/PTT effect under the irradiation of near-infrared light. The synergistic PDT/PTT effect can effectively exhaust keratinocytes and immune cells in the epidermis and dermis, reduce the release of inflammatory cytokines, and relieve the symptoms of psoriasis. This unique functional cell membrane nanovesicles combined with bioorthogonal targeting is applied to enhance the PDT/PTT effect in psoriasis and may provide a solution for the clinical treatment of other inflammatory skin diseases.

Mast Cell Cytokines IL-1, IL-33, and IL-36 Mediate Skin Inflammation in Psoriasis: A Novel Therapeutic Approach with the Anti-Inflammatory Cytokines IL-37, IL-38, and IL-1Ra.

Psoriasis (PS) is a skin disease with autoimmune features mediated by immune cells, which typically presents inflammatory erythematous plaques, and is associated with many comorbidities. PS exhibits excessive keratinocyte proliferation, and a high number of immune cells, including macrophages, neutrophils, Th1 and Th17 lymphocytes, and mast cells (MCs). MCs are of hematopoietic origin, derived from bone marrow cells, which migrate, mature, and reside in vascularized tissues. They can be activated by antigen-provoking overexpression of proinflammatory cytokines, and release a number of mediators including interleukin (IL)-1 and IL-33. IL-1, released by activated keratinocytes and MCs, stimulates skin macrophages to release IL-36—a powerful proinflammatory IL-1 family member. IL-36 mediates both innate and adaptive immunity, including chronic proinflammatory diseases such as psoriasis. Suppression of IL-36 could result in a dramatic improvement in the treatment of psoriasis. IL-36 is inhibited by IL-36Ra, which binds to IL-36 receptor ligands, but suppression can also occur by binding IL-38 to the IL-36 receptor (IL-36R). IL-38 specifically binds only to IL-36R, and inhibits human mononuclear cells stimulated with IL-36 in vitro, sharing the effect with IL-36Ra. Here, we report that inflammation in psoriasis is mediated by IL-1 generated by MCs—a process that activates macrophages to secrete proinflammatory IL-36 inhibited by IL-38. IL-37 belongs to the IL-1 family, and broadly suppresses innate inflammation via IL-1 inhibition. IL-37, in murine models of inflammatory arthritis, causes the suppression of joint inflammation through the inhibition of IL-1. Therefore, it is pertinent to think that IL-37 can play an inhibitory role in inflammatory psoriasis. In this article, we confirm that IL-38 and IL-37 cytokines emerge as inhibitors of inflammation in psoriasis, and hold promise as an innovative therapeutic tool.

Tuhuaiyin alleviates imiquimod-induced psoriasis via inhibiting the properties of IL-17-producing cells and remodels the gut microbiota

Backgroundpsoriasis is a chronic inflammatory skin disease. The accumulation of IL-17 cytokines in the lesions leads to epidermis proliferation. Traditional Chinese medicine has a significant effect on psoriasis treatment. Among them, Tuhuaiyin is a representative prescription, which has an outstanding curative effect in acute and remission stage. MethodsTo reveal the target and molecular mechanism of Tuhuaiyin, systematic pharmacology platform and database screening were used to construct the Tuhuaiyin interaction network with compounds, targets and diseases. The intervention of Tuhuaiyin on keratinocyte proliferation and inflammation was verified in the model of psoriasis-like lesions induced by imiquimod. The effect on the number and function of IL-17-producing cells was detected, and the regulatory effect of Tuhuaiyin on gut microbial was explored. Results32 selected active molecules in Tuhuaiyin acted on psoriasis biological processes. Tuhuaiyin significantly alleviates erythema and scales in the psoriasis like mouse model induced by imiquimod. Excessive proliferation of keratinocytes and infiltration of inflammatory cells were restrained in the dermis by using Tuhuaiyin. The expression of IL-17 was down-regulated in skin and peripheral blood. The proportion of IL-17-producing cells was decreased in immune organs. And phosphorylation of JNK inhibited in skin lesions. At the same time, the change of gut microbial diversity in the psoriasis-like model was improved. Conclusionour study predicted and verified the molecular immunological mechanism of Tuhuaiyin, alleviated the abnormal proliferation of keratinocytes by inhibiting the proportion of IL-17-producing cells and the expression of IL-17 cytokines. Taken together, our data identify the therapeutic potential of Tuhuaiyin for psoriasis.

Epigenetics in psoriasis: perspective of DNA methylation.

Psoriasis is a chronic inflammatory skin disease characterized by excessive proliferation of keratinocytes (KCs). Onset of psoriasis is related to genetic, immune and environmental factors. The environment can interact with the genome through epigenetic modifications, including DNA methylation, and this modification is involved in the pathogenesis of psoriasis. In addition to a skin disease, psoriasis is also considered a systemic disease. We reviewed the current literature of psoriatic DNA methylation for studies from several aspects on the DNA methylation distribution patterns in different tissues/cells, single-nucleotide polymorphisms, and candidate disease genes and identified target genes regulated by DNA methylation that have been directly/indirectly validated. This review contributes to a comprehensive understanding of the important a role that DNA methylation plays in psoriasis from a holistic perspective and will promote the implementation of DNA methylation in diagnostic and therapeutic strategies for psoriatic patients.