RESUMEN

BACKGROUND: Abnormal biological behaviour of keratinocytes (KCs) is a critical pathophysiological manifestation of psoriasis. Ferroptosis is programmed cell death induced by the accumulation of lipid reactive oxygen species (ROS) in the presence of increased intracellular iron ions or inhibition of GPX4. OBJECTIVES: The purpose of this study was to investigate the effects of ferroptosis on the biological behaviour of Keratinocytes (KCs) in psoriasis vulgaris and its possible regulatory mechanisms in clinical samples, cells, and mouse models. METHODS: We first examined the differences in the expression of GPX4 and 4-HNE between psoriasis and normal human lesions. And detected KRT6, FLG, and inflammatory cytokines after inducing ferroptosis in animal and cell models by RT-qPCR, Western blot, immunohistochemistry, and flow cytometry. RESULTS: We found that GPX4 was decreased and that the oxidation product 4-hydroxy-2-nonenal (HNE) was increased in the skin lesions of patients with psoriasis vulgaris. The expression level of GPX4 correlates with the severity of skin lesions. Moreover, inducing ferroptosis promoted the expression of FLG and reduced the expression of KRT6 and inflammatory cytokines in vitro, and alleviated the phenotype of skin lesions in vivo. LIMITATIONS: Our study has limitations, notably small sample size. Larger clinical trials are necessary to investigate the association between ferroptosis and disease progression further. More research is necessary to explore how the ferroptosis inducer RSL3 regulates the abnormal biological behaviour of KCs at both cellular and animal levels and establish ferroptosis inhibitors as controls. CONCLUSIONS: This study confirms the existence of ferroptosis in psoriatic lesions, which may be inversely correlated with disease severity. The ferroptosis inducer RSL3 ameliorated psoriatic symptoms by improving the abnormal biological behaviour of KCs.

Asunto(s)

Modelos Animales de Enfermedad , Ferroptosis , Queratinocitos , Fosfolípido Hidroperóxido Glutatión Peroxidasa , Psoriasis , Psoriasis/patología , Psoriasis/metabolismo , Psoriasis/inmunología , Ferroptosis/fisiología , Queratinocitos/metabolismo , Queratinocitos/patología , Humanos , Animales , Ratones , Proyectos Piloto , Fosfolípido Hidroperóxido Glutatión Peroxidasa/metabolismo , Fosfolípido Hidroperóxido Glutatión Peroxidasa/genética , Aldehídos/metabolismo , Femenino , Masculino , Adulto , Queratina-6/metabolismo , Citocinas/metabolismo , Piel/patología , Piel/metabolismo , Piel/inmunología , Persona de Mediana Edad , Resorcinoles/farmacología , Especies Reactivas de Oxígeno/metabolismo , Carbolinas

RESUMEN

The plasma membrane protein caveolin-1 (CAV-1) regulates signaling by inhibiting a wide range of kinases and other enzymes. Our previous study demonstrated that the downregulation of CAV-1 in psoriatic epidermal cells contributes to inflammation by enhancing JAK/STAT signaling, cell proliferation, and chemokine production. Administration of the CAV-1 scaffolding domain (CSD) peptide suppressed imiquimod (IMQ)-induced psoriasis-like dermatitis. To identify an optimal therapeutic peptide derived from CAV-1, we have compared the efficacy of CSD and subregions of CSD that have been modified to make them water soluble. We refer to these modified peptides as sCSD, sA, sB, and sC. In IMQ-induced psoriasis-like dermatitis, while all four peptides showed major beneficial effects, sB caused the most significant improvements of skin phenotype and number of infiltrating cells, comparable or superior to the effects of sCSD. Phosphorylation of STAT3 was also inhibited by sB. Furthermore, sB suppressed angiogenesis both in vivo in the dermis of IMQ-induced psoriasis mice and in vitro by blocking the ability of conditioned media derived from CAV-1-silenced keratinocytes to inhibit tube formation by HUVEC. In conclusion, sB had similar or greater beneficial effects than sCSD not only by cytokine suppression but by angiogenesis inhibition adding to its ability to target psoriatic inflammation.

Asunto(s)

Caveolina 1 , Citocinas , Imiquimod , Neovascularización Patológica , Psoriasis , Factor de Transcripción STAT3 , Psoriasis/tratamiento farmacológico , Psoriasis/inducido químicamente , Psoriasis/patología , Psoriasis/metabolismo , Caveolina 1/metabolismo , Animales , Ratones , Citocinas/metabolismo , Humanos , Factor de Transcripción STAT3/metabolismo , Neovascularización Patológica/tratamiento farmacológico , Neovascularización Patológica/metabolismo , Péptidos/farmacología , Péptidos/química , Piel/efectos de los fármacos , Piel/metabolismo , Piel/patología , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Modelos Animales de Enfermedad , Agua/química , Solubilidad , Células Endoteliales de la Vena Umbilical Humana/efectos de los fármacos , Angiogénesis

RESUMEN

As potent pro-inflammatory mediators, IL-17 family cytokines play crucial roles in the pathogenesis of various inflammatory and autoimmune skin disorders. Although substantial progress has been achieved in understanding the pivotal role of IL-17A signaling in psoriasis, leading to the development of highly effective biologics, the functions of other IL-17 family members in inflammatory or autoimmune skin diseases remain less explored. In this review, we provide a comprehensive overview of IL-17 family cytokines and their receptors, with a particular focus on the recent advancements in identifying cellular sources, receptors and signaling pathways regulated by these cytokines. At the end, we discuss how the aberrant functions of IL-17 family cytokines contribute to the pathogenesis of diverse inflammatory or autoimmune skin diseases.

Asunto(s)

Enfermedades Autoinmunes , Interleucina-17 , Transducción de Señal , Enfermedades de la Piel , Humanos , Interleucina-17/metabolismo , Interleucina-17/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/metabolismo , Animales , Enfermedades de la Piel/inmunología , Enfermedades de la Piel/metabolismo , Psoriasis/inmunología , Psoriasis/metabolismo , Inflamación/inmunología , Inflamación/metabolismo , Receptores de Interleucina-17/metabolismo , Receptores de Interleucina-17/inmunología

RESUMEN

(1): Atopic dermatitis and psoriasis vulgaris are chronic, inflammatory diseases. Clinical presentation usually leads to a proper diagnosis, but sometimes neither clinical examination nor histopathological evaluation can be conclusive. Therefore, we aimed to build up a novel diagnostic tool and check it for accuracy. The main objective of our work was to differentiate between healthy skin (C), atopic dermatitis (AD) and psoriasis vulgaris (PV) biopsies on the base of involucrin (IVL) and human ß-defensin-2 (hBD-2) concentrations and their mRNA, as well as mRNA for TPP2 and PSMB8. (2): ELISA for IVL and hBD-2 proteins and Real-time PCR for the relative expression of mRNA for: IVL (IVL mRNA), hBD-2 (hBD-2 mRNA), PSMB8 (PSMB8 mRNA) and TPP2 (TPP2 mRNA), isolated from skin biopsies taken from AD and PV patients and healthy volunteers were performed. (3): hBD-2 mRNA and PSMB8 mRNA correlated with some parameters of clinical assessment of inflammatory disease severity. hBD-2 mRNA expression, exclusively, was sufficient to distinguish inflammatory skin biopsies from the healthy ones. (4): hBD-2 mRNA and PSMB8 mRNA analysis were the most valuable parameters in differentiating AD and PV biopsies.

Asunto(s)

Dermatitis Atópica , Psoriasis , ARN Mensajero , Piel , beta-Defensinas , Humanos , Psoriasis/genética , Psoriasis/metabolismo , Psoriasis/patología , Psoriasis/diagnóstico , beta-Defensinas/genética , beta-Defensinas/metabolismo , Dermatitis Atópica/genética , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Dermatitis Atópica/diagnóstico , ARN Mensajero/genética , ARN Mensajero/metabolismo , Biopsia , Femenino , Masculino , Piel/metabolismo , Piel/patología , Adulto , Persona de Mediana Edad , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Diagnóstico Diferencial , Adulto Joven , Adolescente

RESUMEN

Psoriasis is a chronic inflammatory skin condition with numerous causes, including genetic, immunological and infectious factors. The course of psoriasis is long and recurrence is common; pathogenesis is not completely understood. However, there is an association between advancement of psoriasis and aberrant microRNA (miR or miRNA)­155 expression. Through bioinformatics, the present study aimed to analyze the differentially expressed genes and miRNAs in psoriasis and its biological mechanism and function psoriatic inflammation. First of all, differentially expressed genes (DEGs) and miRNAs (DEMs) in patients with psoriasis were identified using GEO2R interactive web application. A psoriasis inflammatory model was established using lipopolysaccharide (LPS)­treated HaCaT keratinocytes, which were transfected with miR­155 mimic or inhibitor. Cell Counting Kit­8 was used for the assessment of cell viability and proliferation, and changes in the cell cycle were examined using flow cytometry. ELISA and reverse transcription­quantitative PCR (RT­qPCR) were used to detect the expression levels of the inflammatory factors IL­1ß and IL­6. The dual­luciferase reporter assay was used to verify the targeting association between miR­155­5p and IFN regulatory factor 2 binding protein 2 (IRF2BP2). To verify the targeting association of miR­155 and the IRF2BP2/kruppel­like factor 2 (KLF2)/NF­κB signaling pathway, expression levels of IRF2BP2, KLF2 and p65 were identified by RT­qPCR and western blotting. IRF2BP2 levels were also confirmed by immunofluorescence, in conjunction with bioinformatics database analysis. Overexpression of miR­155 inhibited proliferation of HaCaT cells and increased the number of cells in S phase and decreasing number of cells in G1 and G2 phase. In the LPS­induced inflammatory state, miR­155 overexpression heightened the inflammatory response of HaCaT cells while inhibition of miR­155 lessened it. Suppression of inflammatory cytokine expression by miR­155­5p inhibitor was reversed by knockdown of IRF2BP2. miR­155 was shown to interact with IRF2BP2 to negatively regulate its expression, leading to decreased KLF2 expression and increased p65 expression and secretion of inflammatory factors, intensifying the inflammatory response of HaCaT cells. Therefore, miR­155 may contribute to development of psoriasis by inducing tissue and cell damage by increasing the inflammatory response of HaCaT cells via the IRF2BP2/KLF2/NF­κB pathway. In conclusion, the results of the present study offer novel perspectives on the role of miR­155 in the onset and progression of psoriasis.

Asunto(s)

Inflamación , Factores de Transcripción de Tipo Kruppel , MicroARNs , FN-kappa B , Psoriasis , Transducción de Señal , Humanos , MicroARNs/genética , MicroARNs/metabolismo , Factores de Transcripción de Tipo Kruppel/genética , Factores de Transcripción de Tipo Kruppel/metabolismo , Psoriasis/genética , Psoriasis/metabolismo , Psoriasis/patología , FN-kappa B/metabolismo , Transducción de Señal/genética , Inflamación/genética , Inflamación/metabolismo , Inflamación/patología , Células HaCaT , Proliferación Celular/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Regulación de la Expresión Génica , Queratinocitos/metabolismo , Lipopolisacáridos/farmacología , Proteínas de Unión al ADN , Factores de Transcripción

RESUMEN

Psoriasis is a chronic, proliferative, and inflammatory skin disease closely associated with inflammatory cytokine production. Cyclophilin A (CypA) is an important proinflammatory factor; however, its role in psoriasis remains unclear. The present data indicate that CypA levels are increased in the lesion skin and serum of patients with psoriasis, which is positively correlated with the psoriasis area severity index. Furthermore, extracellular CypA (eCypA) triggered psoriasis-like inflammatory responses in keratinocytes. Moreover, anti-CypA mAb significantly reduced pathological injury, keratinocyte proliferation, cytokine expression in imiquimod-induced mice. Notably, the therapeutic effect of anti-CypA mAb was better than that of the clinically used anti-IL-17A mAb and methotrexate. Mechanistically, eCypA binds to ACE2 and CD147 and is blocked by anti-CypA mAb. eCypA not only induces the dimerization and phosphorylation of ACE2 to trigger the JAK1/STAT3 signaling pathway for cytokine expression but also interacts with CD147 to promote PI3K/AKT/mTOR signaling-mediated keratinocyte proliferation. These findings demonstrate that the binding of eCypA to ACE2 and CD147 cooperatively triggers psoriasis-like inflammation and anti-CypA mAb is a promising candidate for the treatment of psoriasis.

Asunto(s)

Enzima Convertidora de Angiotensina 2 , Basigina , Ciclofilina A , Queratinocitos , Unión Proteica , Psoriasis , Transducción de Señal , Basigina/metabolismo , Basigina/inmunología , Ciclofilina A/metabolismo , Humanos , Animales , Psoriasis/metabolismo , Psoriasis/inmunología , Ratones , Queratinocitos/metabolismo , Queratinocitos/inmunología , Enzima Convertidora de Angiotensina 2/metabolismo , Inflamación/metabolismo , Inflamación/inmunología , Modelos Animales de Enfermedad , Masculino , Femenino , Proliferación Celular , Anticuerpos Monoclonales/farmacología , Anticuerpos Monoclonales/uso terapéutico , Citocinas/metabolismo

RESUMEN

Dendritic cells (DCs) are crucial in initiating and shaping both innate and adaptive immune responses. Clinical studies and experimental models have highlighted their significant involvement in various autoimmune diseases, positioning them as promising therapeutic targets. Nicotinamide (NAM), a form of vitamin B3, with its anti-inflammatory properties, has been suggested, while the involvement of NAM in DCs regulation remains elusive. Here, through analyzing publicly available databases, we observe substantial alterations in NAM levels and NAM metabolic pathways during DCs activation. Furthermore, we discover that NAM, but not Nicotinamide Mononucleotide (NMN), significantly inhibits DCs over-activation in vitro and in vivo. The suppression of DCs hyperactivation effectively alleviates symptoms of psoriasis. Mechanistically, NAM impairs DCs activation through a Poly (ADP-ribose) polymerases (PARPs)-NF-κB dependent manner. Notably, phosphoribosyl transferase (NAMPT) and PARPs are significantly upregulated in lipopolysaccharide (LPS)-stimulated DCs and psoriasis patients; elevated NAMPT and PARPs expression in psoriasis patients correlates with higher psoriasis area and severity index (PASI) scores. In summary, our findings underscore the pivotal role of NAM in modulating DCs functions and autoimmune disorders. Targeting the NAMPT-PARP axis emerges as a promising therapeutic approach for DC-related diseases.

Asunto(s)

Enfermedades Autoinmunes , Células Dendríticas , Niacinamida , Nicotinamida Fosforribosiltransferasa , Poli(ADP-Ribosa) Polimerasas , Psoriasis , Transducción de Señal , Células Dendríticas/efectos de los fármacos , Células Dendríticas/metabolismo , Células Dendríticas/inmunología , Niacinamida/farmacología , Humanos , Transducción de Señal/efectos de los fármacos , Animales , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Psoriasis/metabolismo , Enfermedades Autoinmunes/tratamiento farmacológico , Nicotinamida Fosforribosiltransferasa/metabolismo , Ratones , Poli(ADP-Ribosa) Polimerasas/metabolismo , FN-kappa B/metabolismo , Ratones Endogámicos C57BL , Lipopolisacáridos

RESUMEN

Conventional histopathological features of psoriasis and atopic dermatitis often overlap. We aimed to investigate Galectin-3 (Gal-3) expression in psoriatic skin lesions and its potential as an immunohistochemical marker for distinguishing between psoriasis and atopic dermatitis on a pathological basis. Based on immunohistochemical analysis, we assessed Gal-3 expression in formalin-fixed, paraffin-embedded tissue sections from 21 patients with psoriasis and 15 patients with atopic dermatitis. Quantitative analysis of expression intensity was performed using the average density (average optical density) method. We analysed the relationship between Gal-3 expression and clinical characteristics, as well as conventional histopathological features. Patients with psoriasis exhibited significantly decreased Gal-3 expression in the epidermis (0.11±0.05) compared to the atopic dermatitis group (0.36±0.15) and healthy controls (0.49±0.13) (p<0.0001). Reduction in Gal-3 expression in the psoriatic epidermis around areas of neutrophil aggregation was more pronounced than around areas of non-neutrophil aggregation (0.07±0.02 vs 0.16±0.05, p<0.01). In both psoriasis (r=-0.48, p<0.05) and atopic dermatitis groups (r=-0.70, p<0.01), Gal-3 expression negatively correlated with epidermal thickness. When epidermal thickness was matched between the two groups, the decrease in epidermal Gal-3 expression remained significant in the psoriasis group compared to the atopic dermatitis group (0.14±0.05 Vs 0.30±0.07, p<0.01). Patients with psoriasis show specific downregulation of epidermal Gal-3, correlating with epidermal thickness and neutrophil-related factors. Gal-3 may serve as an auxiliary discriminative marker between psoriasis and atopic dermatitis, potentially associated with keratinocyte proliferation and neutrophil function.

Asunto(s)

Dermatitis Atópica , Epidermis , Galectina 3 , Psoriasis , Humanos , Psoriasis/metabolismo , Psoriasis/patología , Epidermis/metabolismo , Epidermis/patología , Galectina 3/metabolismo , Galectina 3/análisis , Femenino , Masculino , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Adulto , Persona de Mediana Edad , Biomarcadores/metabolismo , Biomarcadores/análisis , Inmunohistoquímica , Estudios de Casos y Controles , Adulto Joven , Anciano , Diagnóstico Diferencial

RESUMEN

Psoriasis is a common chronic inflammatory skin disease that significantly impacts the patients' quality of life. Recent studies highlighted the function of the interleukin (IL)-1 family member IL-38 in skin homeostasis and suggested an anti-inflammatory role for this cytokine in psoriasis. In this study, we generated mice specifically overexpressing the IL-38 protein in epidermal keratinocytes. We confirmed IL-38 overexpression in the skin by Western blotting. We further detected the protein by ELISA in the plasma, as well as in conditioned media of skin explants isolated from IL-38 overexpressing mice, indicating that IL-38 produced in the epidermis is released from keratinocytes and can be found in the circulation. Unexpectedly, epidermal IL-38 overexpression did not impact the global severity of imiquimod (IMQ)-induced skin inflammation, Similarly, keratinocyte activation and differentiation in IMQ-treated skin were not affected by increased IL-38 expression and there was no global effect on local or systemic inflammatory responses. Nevertheless, we observed a selective inhibition of CXCL1 and IL-6 production in response to IMQ in IL-38 overexpressing skin, as well as reduced Ly6g mRNA levels, suggesting decreased neutrophil infiltration. Epidermal IL-38 overexpression also selectively affected the desquamation process during IMQ-induced psoriasis, as illustrated by reduced plaque formation. Taken together, our results validate the generation of a new mouse line allowing for tissue-specific IL-38 overexpression. Interestingly, epidermal IL-38 overexpression selectively affected specific disease-associated readouts during IMQ-induced psoriasis, suggesting a more complex role of IL-38 in the inflamed skin than previously recognized. In particular, our data highlight a potential involvement of IL-38 in the regulation of skin desquamation.

Asunto(s)

Imiquimod , Interleucina-1 , Queratinocitos , Psoriasis , Animales , Queratinocitos/metabolismo , Queratinocitos/inmunología , Ratones , Psoriasis/inducido químicamente , Psoriasis/inmunología , Psoriasis/metabolismo , Interleucina-1/metabolismo , Interleucina-1/genética , Piel/inmunología , Piel/patología , Piel/metabolismo , Modelos Animales de Enfermedad , Ratones Transgénicos , Ratones Endogámicos C57BL

RESUMEN

In recent years, the incidence of metabolic syndrome (MS) has increased due to lifestyle-related factors in developed countries. MS represents a group of conditions that increase the risk of diabetes, cardiovascular diseases, and other severe health problems. Low-grade chronic inflammation is now considered one of the key aspects of MS and could be defined as a new cardiovascular risk factor. Indeed, an increase in visceral adipose tissue, typical of obesity, contributes to the development of an inflammatory state, which, in turn, induces the production of several proinflammatory cytokines responsible for insulin resistance. Psoriasis is a chronic relapsing inflammatory skin disease and is characterized by the increased release of pro-inflammatory cytokines, which can contribute to different pathological conditions within the spectrum of MS. A link between metabolic disorders and Psoriasis has emerged from evidence indicating that weight loss obtained through healthy diets and exercise was able to improve the clinical course and therapeutic response of Psoriasis in patients with obesity or overweight patients and even prevent its occurrence. A key factor in this balance is the gut microbiota; it is an extremely dynamic system, and this makes its manipulation through diet possible via probiotic, prebiotic, and symbiotic compounds. Given this, the gut microbiota represents an additional therapeutic target that can improve metabolism in different clinical conditions.

Asunto(s)

Microbioma Gastrointestinal , Inflamación , Síndrome Metabólico , Psoriasis , Psoriasis/microbiología , Psoriasis/metabolismo , Psoriasis/complicaciones , Humanos , Síndrome Metabólico/microbiología , Síndrome Metabólico/metabolismo , Síndrome Metabólico/complicaciones , Inflamación/metabolismo , Animales , Obesidad/complicaciones , Obesidad/microbiología , Obesidad/metabolismo

RESUMEN

Atopic dermatitis and psoriasis are prevalent inflammatory skin conditions that significantly impact the quality of life of patients, with diverse treatment options available. Despite advances in understanding their underlying mechanisms, recent research highlights the significance of interleukins IL-18 and IL-37, in Th1, Th2, and Th17 inflammatory responses, closely associated with the pathogenesis of psoriasis and atopic dermatitis. Hence, IL-18 and IL-37 could potentially become therapeutic targets. This narrative review synthesizes knowledge on these interleukins, their roles in atopic dermatitis and psoriasis, and emerging treatment strategies. Findings of a literature search up to 30 May 2024, underscore a research gap in IL-37-targeted therapies. Conversely, IL-18-focused treatments have demonstrated promise in adult-onset Still's Disease, warranting further exploration for their potential efficacy in psoriasis and atopic dermatitis.

Asunto(s)

Dermatitis Atópica , Interleucina-18 , Interleucina-1 , Psoriasis , Humanos , Dermatitis Atópica/inmunología , Dermatitis Atópica/tratamiento farmacológico , Dermatitis Atópica/etiología , Dermatitis Atópica/metabolismo , Psoriasis/tratamiento farmacológico , Psoriasis/inmunología , Psoriasis/metabolismo , Interleucina-18/metabolismo , Interleucina-1/metabolismo , Interleucina-1/antagonistas & inhibidores , Animales , Terapia Molecular Dirigida

RESUMEN

Rare mutations in CARD14 promote psoriasis by inducing CARD14-BCL10-MALT1 complexes that activate NF-κB and MAP kinases. Here, the downstream signalling mechanism of the highly penetrant CARD14E138A alteration is described. In addition to BCL10 and MALT1, CARD14E138A associated with several proteins important in innate immune signalling. Interactions with M1-specific ubiquitin E3 ligase HOIP, and K63-specific ubiquitin E3 ligase TRAF6 promoted BCL10 ubiquitination and were essential for NF-κB and MAP kinase activation. In contrast, the ubiquitin binding proteins A20 and ABIN1, both genetically associated with psoriasis development, negatively regulated signalling by inducing CARD14E138A turnover. CARD14E138A localized to early endosomes and was associated with the AP2 adaptor complex. AP2 function was required for CARD14E138A activation of mTOR complex 1 (mTORC1), which stimulated keratinocyte metabolism, but not for NF-κB nor MAP kinase activation. Furthermore, rapamycin ameliorated CARD14E138A-induced keratinocyte proliferation and epidermal acanthosis in mice, suggesting that blocking mTORC1 may be therapeutically beneficial in CARD14-dependent psoriasis.

Asunto(s)

Proteínas Adaptadoras de Señalización CARD , Proliferación Celular , Endosomas , Queratinocitos , Diana Mecanicista del Complejo 1 de la Rapamicina , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Diana Mecanicista del Complejo 1 de la Rapamicina/genética , Humanos , Animales , Queratinocitos/metabolismo , Ratones , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Endosomas/metabolismo , Transducción de Señal , Psoriasis/metabolismo , Psoriasis/patología , Psoriasis/genética , Proteínas de la Membrana/metabolismo , Proteínas de la Membrana/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Proteínas Adaptadoras Transductoras de Señales/genética , FN-kappa B/metabolismo , FN-kappa B/genética , Proteína 10 de la LLC-Linfoma de Células B/metabolismo , Proteína 10 de la LLC-Linfoma de Células B/genética , Ubiquitinación , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genética , Factor 6 Asociado a Receptor de TNF/metabolismo , Factor 6 Asociado a Receptor de TNF/genética , Ubiquitina-Proteína Ligasas/metabolismo , Ubiquitina-Proteína Ligasas/genética , Células HEK293 , Transporte de Proteínas , Guanilato Ciclasa

RESUMEN

Psoriasis is a prevalent chronic inflammatory and immunological disorder. Its lesions are present as scaly erythema or plaques. Disruptions in the body's immune system play a significant role in developing psoriasis. Recent evidence suggests a potential role of the gut microbiome in autoimmune diseases. Short-chain fatty acids (SCFAs) are the primary metabolites created by gut microbes and play a crucial fuction in autoimmunity. SCFAs act on various cells by mediating signaling to participate in host physiological and pathological processes. These processes encompass body metabolism, maintenance of intestinal barrier function, and immune system modulation. SCFAs can regulate immune cells to enhance the body's immune function, potentially influencing the prevention and treatment of psoriasis. However, the mechanisms underlying the role of SCFAs in psoriasis remain incompletely understood. This paper examines the relationship between SCFAs and psoriasis, elucidating how SCFAs influence the immune system, inflammatory response, and gut barrier in psoriasis. According to the study, in psoriasis, SCFAs have been shown to regulate neutrophils, macrophages, and dendritic cells in the adaptive immune system, as well as T and B cells in the innate immune system. Additionally, we explore the role of SCFAs in psoriasis by maintaining intestinal barrier function, restoring intestinal ecological homeostasis, and investigating the potential therapeutic benefits of SCFAs for psoriasis.

Asunto(s)

Ácidos Grasos Volátiles , Microbioma Gastrointestinal , Psoriasis , Psoriasis/inmunología , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Humanos , Ácidos Grasos Volátiles/metabolismo , Ácidos Grasos Volátiles/uso terapéutico , Animales , Microbioma Gastrointestinal/inmunología , Inmunidad Innata

RESUMEN

Psoriasis is a multifactorial, chronic inflammatory skin disease with unresolved questions on its primary events. Iron overload has been described in the epidermis of psoriasis patients, but its relevance remains unknown. We found that the key iron regulatory hormone hepcidin was highly expressed in the epidermis of psoriasis patients, especially the pustular variants resistant to treatments. In a murine model of acute skin inflammation, keratinocyte-derived hepcidin was required for iron retention in keratinocytes, leading to hyperproliferation of the epidermal layer and neutrophil recruitment, two main features of psoriatic skin lesions. Keratinocytes overexpressing hepcidin were sufficient to elicit these psoriasiform features in a transgenic mouse model. Furthermore, transcriptome analysis of these keratinocytes revealed canonical pathways found in human psoriasis, pointing to a causal role for hepcidin in the pathogenesis of the disease. Altogether, our data suggest that hepcidin could be an actionable target for skin psoriasis treatment, in addition to current therapeutics, or targeted as maintenance therapy during remission to prevent recurrence.

Asunto(s)

Proliferación Celular , Hepcidinas , Hierro , Queratinocitos , Ratones Transgénicos , Infiltración Neutrófila , Psoriasis , Piel , Hepcidinas/metabolismo , Hepcidinas/genética , Psoriasis/metabolismo , Psoriasis/patología , Animales , Queratinocitos/metabolismo , Humanos , Hierro/metabolismo , Ratones , Piel/metabolismo , Piel/patología , Modelos Animales de Enfermedad , Masculino , Femenino , Epidermis/metabolismo , Epidermis/patología , Ratones Endogámicos C57BL , Inflamación/metabolismo , Inflamación/patología

RESUMEN

Knowledge about the molecular mechanisms underlying the systemic inflammation observed in psoriasis remains incomplete. In this study, we applied mass spectrometry-based proteomics to compare the plasma protein levels between patients with psoriasis and healthy individuals, aiming to unveil potential systemically dysregulated proteins and pathways associated with the disease. Plasma samples from adult patients with moderate-to-severe psoriasis vulgaris (N = 59) and healthy age- and sex-matched individuals (N = 21) were analyzed using liquid chromatography-tandem mass spectrometry. Patients did not receive systemic anti-psoriatic treatment for four weeks before inclusion. A total of 776 protein groups were quantified. Of these, 691 were present in at least 60% of the samples, providing the basis for the downstream analysis. We identified 20 upregulated and 22 downregulated proteins in patients with psoriasis compared to controls (p < 0.05). Multiple proteins from the complement system were upregulated, including C2, C4b, C5, and C9, and pathway analysis revealed enrichment of proteins involved in complement activation and formation of the terminal complement complex. On the other end of the spectrum, periostin was the most downregulated protein in sera from patients with psoriasis. This comprehensive proteomic investigation revealed significantly elevated levels of complement cascade proteins in psoriatic plasma, which might contribute to increased systemic inflammation in patients with psoriasis.

Asunto(s)

Proteínas del Sistema Complemento , Proteómica , Psoriasis , Humanos , Psoriasis/sangre , Psoriasis/metabolismo , Masculino , Femenino , Proteómica/métodos , Adulto , Proteínas del Sistema Complemento/metabolismo , Persona de Mediana Edad , Estudios de Casos y Controles , Espectrometría de Masas en Tándem , Proteoma/metabolismo , Biomarcadores/sangre , Cromatografía Liquida

RESUMEN

Caspase recruitment domain family member 14 (CARD14) and its variants are associated with both atopic dermatitis (AD) and psoriasis, but their mechanistic impact on skin barrier homeostasis is largely unknown. CARD14 is known to signal via NF-κB; however, CARD14-NF-κB signaling does not fully explain the heterogeneity of CARD14-driven disease. Here, we describe a direct interaction between CARD14 and MYC and show that CARD14 signals through MYC in keratinocytes to coordinate skin barrier homeostasis. CARD14 directly binds MYC and influences barrier formation in an MYC-dependent fashion, and this mechanism is undermined by disease-associated CARD14 variants. These studies establish a paradigm that CARD14 activation regulates skin barrier function by two distinct mechanisms, including activating NF-κB to bolster the antimicrobial (chemical) barrier and stimulating MYC to bolster the physical barrier. Finally, we show that CARD14-dependent MYC signaling occurs in other epithelia, expanding the impact of our findings beyond the skin.

Asunto(s)

Proteínas Adaptadoras de Señalización CARD , Epidermis , Homeostasis , Queratinocitos , FN-kappa B , Proteínas Proto-Oncogénicas c-myc , Humanos , Proteínas Adaptadoras de Señalización CARD/metabolismo , Proteínas Adaptadoras de Señalización CARD/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Epidermis/metabolismo , Queratinocitos/metabolismo , FN-kappa B/metabolismo , Transducción de Señal , Dermatitis Atópica/metabolismo , Dermatitis Atópica/patología , Dermatitis Atópica/genética , Guanilato Ciclasa/metabolismo , Guanilato Ciclasa/genética , Epitelio/metabolismo , Unión Proteica , Psoriasis/metabolismo , Psoriasis/genética , Psoriasis/patología , Proteínas de la Membrana

RESUMEN

Psoriasis is characterized by keratinocyte (KC) hyperproliferation and inflammatory cell infiltration, but the mechanisms remain unclear. In an imiquimod-induced mouse psoriasiform model, p38 activity is significantly elevated in KCs and p38α specific deletion in KCs ameliorates skin inflammation. p38α signaling promotes KC proliferation and psoriasis-related proinflammatory gene expression during psoriasis development. Mechanistically, p38α enhances KC proliferation and production of inflammatory cytokines and chemokines by activating STAT3. While p38α signaling in KCs does not affect the expression of IL-23 and IL-17, it substantially amplifies the IL-23/IL-17 pathogenic axis in psoriasis. The therapeutic effect of IL-17 neutralization is associated with decreased p38 and STAT3 activities in KCs and targeting the p38α-STAT3 axis in KCs ameliorates the severity of psoriasis. As IL-17 also highly activates p38 and STAT3 in KCs, our findings reveal a sustained signaling circuit important for psoriasis development, highlighting p38α-STAT3 axis as an important target for psoriasis treatment.

Asunto(s)

Proliferación Celular , Citocinas , Queratinocitos , Proteína Quinasa 14 Activada por Mitógenos , Psoriasis , Factor de Transcripción STAT3 , Psoriasis/metabolismo , Psoriasis/genética , Psoriasis/patología , Factor de Transcripción STAT3/metabolismo , Factor de Transcripción STAT3/genética , Queratinocitos/metabolismo , Animales , Ratones , Proteína Quinasa 14 Activada por Mitógenos/metabolismo , Proteína Quinasa 14 Activada por Mitógenos/genética , Citocinas/metabolismo , Regulación hacia Abajo , Ratones Noqueados , Interleucina-17/metabolismo , Interleucina-17/genética , Ratones Endogámicos C57BL , Modelos Animales de Enfermedad , Transducción de Señal , Humanos , Imiquimod

RESUMEN

Psoriasis is a chronic inflammatory skin disorder with various subtypes, including psoriasis vulgaris (PV) and palmoplantar pustulosis (PPP). Metabolomics studies have provided insights into psoriasis pathogenesis. However, research on metabolomic alterations in PV and PPP patients is limited. We aimed to explore and compare the metabolic profiles of patients with PV and PPP to those of healthy volunteers (HVs). A single-centre retrospective cohort was constructed, comprising Korean patients with psoriasis and HVs matched by age and sex. Clinical information including demographics, disease severity, and comorbidities were collected. Plasma samples were subjected to targeted metabolic analysis using an Absolute IDQ®p180 kit, which quantified 188 metabolites, including amino acids and carnitines. Statistical significance was assessed using an independent t-test and chi-square test, with p-values adjusted by the Benjamini-Hochberg procedure. Pathway analyses were employed to gain a comprehensive understanding of the metabolite profile. This study included 93 patients (73 PV and 20 PPP) and an equal number of HVs. PV patients showed increased levels of sarcosine, serotonin, propionylcarnitine, proline, aspartic acid, tyrosine, taurine, spermine and ornithine, but exhibited a decreased level of acetylcarnitine than matched HVs. Notably, sarcosine levels were significantly elevated in PPP patients. Furthermore, the sarcosine/glycine ratio was significantly higher in both PV and PPP patients than in HVs. Pathway analysis showed significant increases in metabolites involved in amino acid metabolism and the urea cycle in PV patients. In conclusion, this study demonstrated distinct metabolic profiles in PV and PPP patients compared to HVs, suggesting sarcosine as a potential biomarker for psoriasis.

Asunto(s)

Psoriasis , Humanos , Psoriasis/sangre , Psoriasis/metabolismo , Masculino , Femenino , Persona de Mediana Edad , Adulto , Estudios Retrospectivos , Metabolómica , Anciano , Estudios de Casos y Controles , Metaboloma , Sarcosina/sangre , Carnitina/sangre , Carnitina/análogos & derivados , Carnitina/metabolismo , Aminoácidos/sangre , Aminoácidos/metabolismo , Índice de Severidad de la Enfermedad

RESUMEN

BACKGROUND: Psoriasis is a chronic inflammatory skin disease that can cause systemic inflammation in various organs. Rutin has been suggested to fight psoriasis, but the signaling pathways by which it works need to be explored. MATERIALS AND METHODS: HaCaT cells co-stimulated with interleukin (IL)-17, IL-22, tumor necrosis factor-alpha (TNF-α), IL-1α, and oncostatin M (M5) were used as an in vitro cell model of psoriasis. The proliferation and viability of HaCaT cells were determined by 5-ethynyl-2'-deoxyuridine and cell counting assays. Relative mRNA levels of IL-6, TNF-α, chemokines (CXCL1 and CXCL2), and anti-microbial peptides (S100A7 and S100A8) were detected by reverse transcriptase-quantitative PCR. Release of IL-6 and TNF-α from HaCaT cells was measured by enzyme-linked immunosorbent assay. Keratin1, Keratin5, p-JAK2, and p-STAT3 protein levels were estimated with western blotting. Molecular docking predicted binding sites for Rutin and STAT3. RESULTS: Rutin treatment undercut M5-urged viability increase and proliferation boost in HaCaT cells. Moreover, M5 stimulation mediated upregulation of IL-6, TNF-α, CXCL1, CXCL2, S100A7, and S100A8 was partially reversed after Rutin treatment. In addition, M5 stimulation induced downregulation of Keratin1 and Keratin5 proteins as well as upregulation of p-JAK2 and p-STAT3 proteins were attenuated in response to Rutin treatment, manifesting that Rutin treatment inhibited M5-promoted aberrant differentiation and impaired M5-mediated activation of the JAK2/STAT3 signaling in HaCaT cells. Molecular docking discovered that residues GLN326 and ASP334 in STAT3 might bind to Rutin. CONCLUSION: Rutin treatment blocked the JAK2/STAT3 signaling, thus attenuating psoriasis-related inflammation and anomalous differentiation in keratinocytes.

Asunto(s)

Janus Quinasa 2 , Queratinocitos , Psoriasis , Rutina , Factor de Transcripción STAT3 , Transducción de Señal , Humanos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células HaCaT , Inflamación/metabolismo , Janus Quinasa 2/metabolismo , Queratinocitos/efectos de los fármacos , Queratinocitos/metabolismo , Simulación del Acoplamiento Molecular , Psoriasis/metabolismo , Psoriasis/tratamiento farmacológico , Rutina/farmacología , Transducción de Señal/efectos de los fármacos , Factor de Transcripción STAT3/metabolismo

RESUMEN

Psoriatic disease, encompassing both psoriasis (Pso) and psoriatic arthritis (PsA), is closely intertwined with a significantly elevated risk of developing cardiovascular diseases. This connection is further compounded by a higher prevalence of cardiometabolic comorbidities, including type 2 diabetes, obesity, insulin resistance, arterial hypertension, and dysregulated lipid profiles. These comorbidities exceed the rates seen in the general population and compound the potential for increased mortality among those living with this condition. Recognizing the heightened cardiometabolic risk inherent in psoriatic disease necessitates a fundamental shift in the treatment paradigm. It is no longer sufficient to focus solely on mitigating inflammation. Instead, there is an urgent need to address and effectively manage the metabolic parameters that have a substantial impact on cardiovascular health. Within this context, apremilast emerges as a pivotal treatment option for psoriatic disease. What sets apremilast apart is its dual-action potential, addressing not only inflammation but also the critical metabolic parameters. This comprehensive treatment approach opens up new opportunities to improve the well-being of people living with psoriatic disease. This review delves into the multifaceted aspects involved in the development of cardiovascular disease and its intricate association with psoriatic disease. We then provide an in-depth exploration of the pleiotropic effects of apremilast, highlighting its potential to simultaneously mitigate metabolic complications and inflammation in individuals affected by these conditions.

Asunto(s)

Antiinflamatorios no Esteroideos , Enfermedades Cardiovasculares , Psoriasis , Talidomida , Humanos , Talidomida/análogos & derivados , Talidomida/uso terapéutico , Enfermedades Cardiovasculares/tratamiento farmacológico , Enfermedades Cardiovasculares/prevención & control , Psoriasis/tratamiento farmacológico , Psoriasis/metabolismo , Antiinflamatorios no Esteroideos/uso terapéutico , Artritis Psoriásica/tratamiento farmacológico , Animales