Microneedles with Implantable Tip-Accumulated Therapeutics for the Long-Term Management of Psoriasis.

Methotrexate is successfully used as the gold standard for managing moderate-to-severe psoriasis. However, the low bioavailability and short half-life of the oral pills and the invasiveness of the parenteral injections make these suboptimal therapeutic options. Microneedles, bridging the advantages of the former forms, are successfully used to deliver methotrexate for different therapeutic purposes. However, the utilized dissolving microneedles demand frequent administration, potentially compromising patients' compliance. Additionally, the high toxicity of methotrexate prompts a quest for safer alternatives. Phloretin, a natural compound with confirmed antipsoriatic potential, emerges as a promising candidate. Herein, microneedle patches with separable, slow-degrading tips are developed for the sustained delivery of methotrexate and phloretin, as a comprehensive solution for long-term psoriasis management. Both compounds are individually loaded at varying doses and display sustained-release profiles. The developed microneedle patches demonstrate high mechanical strength, favorable drug delivery efficiency, and remarkable antipsoriatic potential both in vitro in keratinocytes and in vivo in a psoriasis mouse model. Comparative analysis with two subcutaneous injections reveals a similar antipsoriatic efficacy with a single patch of either compound, with prominent phloretin safety. Therefore, the developed patches present a superior alternative to methotrexate's current marketed forms and provide a viable alternative (phloretin) with comparable antipsoriatic efficacy and higher safety.

Antiproliferative and Anti-Inflammatory Effects of the Polyphenols Phloretin and Balsacone C in a Coculture of T Cells and Psoriatic Keratinocytes.

Plaque psoriasis is a chronic inflammatory skin disease causing red inflamed lesions covered by scales. Leukocytes, including dendritic cells and T cells, participate in the inflammation of the skin by producing multiple cytokines, thus contributing to the hyperproliferation of keratinocytes. Lack of effectiveness and toxic side effects are the main concerns with conventional treatments, and research involving new antipsoriatic molecules is essential. In this study, the anti-inflammatory and antiproliferative effects of two natural polyphenols, phloretin and balsacone C, were investigated using the coculture of T cells and psoriatic keratinocytes. Phloretin exerted antiproliferative activity by regulating the expression of antigen Ki67 and proliferating cell nuclear antigen (PCNA). These effects were comparable to those of methotrexate, a reference treatment for moderate to severe psoriasis. With balsacone C, the expression of Ki67 was also reduced. Additionally, phloretin decreased the levels of multiple pro-inflammatory cytokines: monocyte chemoattractant protein-1 (MCP-1/CCL2), macrophage inflammatory protein-1α (MIP-1α), granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-1 alpha (IL-1α), interleukin-1 beta (IL-1ß), interleukin-6 (IL-6), interleukin-17A (IL-17A), and tumor necrosis factor alpha (TNF-α). The increased interleukin-2 (IL-2) levels with phloretin and methotrexate also represented anti-inflammatory activity. Balsacone C and methotrexate decreased the levels of IL-1α and IL-1ß, but methotrexate exerted a higher reduction. In summary, the anti-inflammatory effects of phloretin were more pronounced than those of methotrexate and balsacone C. In addition, the expression of lymphocyte common antigen (CD45) was more similar to that of the healthy condition after using phloretin or methotrexate. Finally, phloretin stood out from the other compounds and appears promising for psoriasis treatment.

Eicosapentaenoic acid reduces the proportion of IL-17A-producing T cells in a 3D psoriatic skin model.

Psoriasis is a skin disease presenting as erythematous lesions with accentuated proliferation of epidermal keratinocytes, infiltration of leukocytes, and dysregulated lipid metabolism. T cells play essential roles in the disease. n-3 polyunsaturated fatty acids are anti-inflammatory metabolites, which exert an immunosuppressive effect on healthy T cells. However, the precise mechanistic processes of n-3 polyunsaturated fatty acids on T cells in psoriasis are still unrevealed. In this study, we aimed to evaluate the action of eicosapentaenoic acid (EPA) on T cells in a psoriatic skin model produced with T cells. A coculture of psoriatic keratinocytes and polarized T cells was prepared using culture media, which was either supplemented with 10 µM EPA or left unsupplemented. Healthy and psoriatic skin substitutes were produced according to the self-assembly method. In the coculture model, EPA reduced the proportion of IL-17A-positive cells, while increasing that of FOXP3-positive cells, suggesting an increase in the polarization of regulatory T cells. In the 3D psoriatic skin model, EPA normalized the proliferation of psoriatic keratinocytes and diminished the levels of IL-17A. The expression of the proteins of the signal transducer and activator of transcription was influenced following EPA supplementation with downregulation of the phosphorylation levels of signal transducer and activator of transcription 3 in the dermis. Finally, the NFκB signaling pathway was modified in the EPA-supplemented substitutes with an increase in Fas amounts. Ultimately, our results suggest that in this psoriatic model, EPA exerts its anti-inflammatory action by decreasing the proportion of IL-17A-producing T cells.

Docosahexaenoic Acid Modulates Paracellular Absorption of Testosterone and Claudin-1 Expression in a Tissue-Engineered Skin Model.

Healthy skin moLEdels produced by tissue-engineering often present a suboptimal skin barrier function as compared with normal human skin. Moreover, skin substitutes reconstructed according to the self-assembly method were found to be deficient in polyunsaturated fatty acids (PUFAs). Therefore, in this study, we investigated the effects of a supplementation of the culture media with docosahexaenoic acid (DHA) on the barrier function of skin substitutes. To this end, 10 µM DHA-supplemented skin substitutes were produced (n = 3), analyzed, and compared with controls (substitutes without supplementation). A Franz cell diffusion system, followed by ultra-performance liquid chromatography, was used to perform a skin permeability to testosterone assay. We then used gas chromatography to quantify the PUFAs found in the epidermal phospholipid fraction of the skin substitutes, which showed successful DHA incorporation. The permeability to testosterone was decreased following DHA supplementation and the lipid profile was improved. Differences in the expression of the tight junction (TJ) proteins claudin-1, claudin-4, occludin, and TJ protein-1 were observed, principally a significant increase in claudin-1 expression, which was furthermore confirmed by Western blot analyses. In conclusion, these results confirm that the DHA supplementation of cell culture media modulates different aspects of skin barrier function in vitro and reflects the importance of n-3 PUFAs regarding the lipid metabolism in keratinocytes.

A Tissue-Engineered Human Psoriatic Skin Model to Investigate the Implication of cAMP in Psoriasis: Differential Impacts of Cholera Toxin and Isoproterenol on cAMP Levels of the Epidermis.

Pathological and healthy skin models were reconstructed using similar culture conditions according to well-known tissue engineering protocols. For both models, cyclic nucleotide enhancers were used as additives to promote keratinocytes' proliferation. Cholera toxin (CT) and isoproterenol (ISO), a beta-adrenergic agonist, are the most common cAMP stimulators recommended for cell culture. The aim of this study was to evaluate the impact of either CT or ISO on the pathological characteristics of the dermatosis while producing a psoriatic skin model. Healthy and psoriatic skin substitutes were produced according to the self-assembly method of tissue engineering, using culture media supplemented with either CT (10-10 M) or ISO (10-6 M). Psoriatic substitutes produced with CT exhibited a more pronounced psoriatic phenotype than those produced with ISO. Indeed, the psoriatic substitutes produced with CT had the thickest epidermis, as well as contained the most proliferating cells and the most altered expression of involucrin, filaggrin, and keratin 10. Of the four conditions under study, psoriatic substitutes produced with CT had the highest levels of cAMP and enhanced expression of adenylate cyclase 9. Taken together, these results suggest that high levels of cAMP are linked to a stronger psoriatic phenotype.

Infiltration of T Cells into a Three-Dimensional Psoriatic Skin Model Mimics Pathological Key Features.

Psoriasis is an autoimmune chronic dermatosis that is T cell-mediated, characterized by epidermal thickening, aberrant epidermal differentiation and inflammatory infiltrates, with a dominant Th1 and Th17 profile. Additional in vitro models are required to study the complex interactions between activated T cells and skin cells, and to develop new, more effective treatments. We have therefore sought to model this psoriatic inflammation by the generation of tissue-engineered immunocompetent tissues, and we have investigated the response of activated T-cell infiltration in models produced with lesional psoriatic skin cells on major hallmarks of psoriasis. The immunocompetent lesional skin model displayed a delayed onset of epidermal differentiation, an hyperproliferation of the basal keratinocytes, a drastic increase in the secretion of proinflammatory cytokines, and a disturbed expression of key transcription factors, as observed in lesional plaques, suggesting a crucial importance of combining the pathological phenotype of cutaneous cells to T cells in order to generate a relevant model for psoriasis. Finally, we found this skin model to be responsive to methotrexate treatment, making it a valuable tool for drug development.

Dihydrochalcone Derivatives from Populus balsamifera L. Buds for the Treatment of Psoriasis.

Psoriasis is a skin disorder characterized by epidermal hyperplasia, hyperkeratosis, and inflammation. The treatments currently available on the market only improve patients' quality of life and are associated with undesirable side effects. Thus, research leading to the development of new, effective, and safer therapeutic agents is still relevant. Populus balsamifera L. buds were used traditionally by Native Americans to treat various skin pathologies such as eczema and psoriasis. In this study, the antipsoriatic activities of dihydrochalcone derivatives from Populus balsamifera L. buds, known as balsacones, were investigated. The experiments were performed in vitro using a psoriatic skin substitute model. Also, anti-inflammatory and antioxidant activities were investigated. The tested balsacones showed promising antipsoriatic properties by slowing down cell growth and by regulating the expression of involucrin, loricrin, and Ki67 better than methotrexate in psoriatic substitutes. All five tested compounds could be an effective topical treatment for psoriasis, with promising anti-inflammatory and antioxidant actions that may contribute to clinical improvement in patients with psoriasis.

The Tissue-Engineered Human Psoriatic Skin Substitute: A Valuable In Vitro Model to Identify Genes with Altered Expression in Lesional Psoriasis.

Psoriasis is a chronic inflammatory skin disease for which no cure has emerged. Its complex etiology requires the development of an in vitro model representative of the pathology. In this study, we exploited gene profiling analyses on microarray in order to characterize and further optimize the production of a human psoriatic skin model representative of this in vivo skin disease. Various skin substitutes were produced by tissue-engineering using biopsies from normal, healthy donors, or from lesional or non-lesional skin samples from patients with psoriasis, and their gene expression profiles were examined by DNA microarray. We demonstrated that more than 3540 and 1088 genes (two-fold change) were deregulated between healthy/lesional and lesional/non-lesional psoriatic substitutes, respectively. Moreover, several genes related to lipid metabolism, such as PLA2G4E and PLA2G4C, were identified as repressed in the lesional substitutes. In conclusion, gene profiling analyses identified a list of deregulated candidate genes associated with various metabolic pathways that may contribute to the progression of psoriasis.

Contribution of In Vivo and Organotypic 3D Models to Understanding the Role of Macrophages and Neutrophils in the Pathogenesis of Psoriasis.

Psoriasis, a common chronic immune-mediated skin disease, is histologically characterized by a rapid keratinocyte turnover and differentiation defects. Key insights favor the idea that T cells are not the only key actors involved in the inflammatory process. Innate immune cells, more precisely neutrophils and macrophages, provide specific signals involved in the initiation and the maintenance of the pathogenesis. Current data from animal models and, to a lesser extent, three-dimensional in vitro models have confirmed the interest in leaning towards other immune cell types as a potential new cellular target for the treatment of the disease. Although these models do not mimic the complex phenotype nor all human features of psoriasis, their development is necessary and essential to better understand reciprocal interactions between skin cells and innate immune cells and to emphasize the crucial importance of the local lesional microenvironment. In this review, through the use of in vivo and 3D organotypic models, we aim to shed light on the crosstalk between epithelial and immune components and to discuss the role of secreted inflammatory molecules in the development of this chronic skin disease.

Impact of the crystal size of crystalline active pharmaceutical compounds on loading into microneedles.

Microneedle (MN) technology offers a promising platform for the delivery of a wide variety of active pharmaceutical compounds into and/or through the skin. Yet, the low loading capacity of MNs limits their clinical translation. The solid state of loaded compounds, crystallinity versus amorphousness and crystal size of the former, could greatly affect their loading. Here, we investigated the effect of the crystal size of crystalline compounds on their loading into dissolving MNs, prepared using the solvent-casting technique. A model crystalline compound was subjected to crystal size reduction via wet bead milling and loaded into dissolving MNs. A range of crystal sizes, from micro to nano, was obtained via different milling periods. The obtained crystals were characterized for their size, morphology, and sedimentation behavior. Besides, their content, solid state inside the MNs, and impact on the MN mechanical strength were assessed. The crystals exhibited size-dependent sedimentation, which dramatically affected their loading inside the MNs. However, crystal size and sedimentation demonstrated a negligible effect on the mechanical strength and sharpness of the needles, hence no anticipated impact on the MNs' drug delivery efficiency. The elucidation of the correlation between the crystal size and MN loading opens new potentials to address a major drawback in MN technology.

Sensory neurons increase keratinocyte proliferation through CGRP release in a tissue engineered in vitro model of innervation in psoriasis.

Skin denervation has been shown to cause remission of psoriatic lesions in patients, which can reappear if reinnervation occurs. This effect can be induced by the activation of dendritic cells through sensory innervation. However, a direct effect of nerves on the proliferation of keratinocytes involved in the formation of psoriatic plaques has not been investigated. We developed, by tissue engineering, a model of psoriatic skin made of patient skin cells that showed increased keratinocyte proliferation and epidermal thickness compared to healthy controls. When this model was treated with CGRP, a neuropeptide released by sensory neurons, an increased keratinocyte proliferation was observed in the psoriatic skin model, but not in the control. When a sensory nerve network was incorporated in the psoriatic model and treated with capsaicin to induce neuropeptide release, an increase of keratinocyte proliferation was confirmed, which was blocked by a CGRP antagonist while no difference was noticed in the innervated healthy control. We showed that sensory neurons can participate directly to keratinocyte hyperproliferation in the formation of psoriatic lesions through the release of CGRP, independently of the immune system. Our unique tissue-engineered innervated psoriatic skin model could be a valuable tool to better understand the mechanism by which nerves may modulate psoriatic lesion formation in humans. STATEMENT OF SIGNIFICANCE: This study shows that keratinocytes extracted from patients' psoriatic skin retain, at least in part, the disease phenotype. Indeed, when combined in a 3D model of tissue-engineered psoriatic skin, keratinocytes exhibited a higher proliferation rate, and produced a thicker epidermis than a healthy skin control. In addition, their hyperproliferation was aggravated by a treatment with CGRP, a neuropeptide released by sensory nerves. In a innervated model of tissue-engineered psoriatic skin, an increase in keratinocyte hyperproliferation was also observed after inducing neurons to release neuropeptides. This effect was prevented by concomitant treatment with an antagonist to CGRP. Thus, this study shows that sensory nerves can directly participate to affect keratinocyte hyperproliferation in psoriasis through CGRP release.

Characterization of the structure of human skin substitutes by infrared microspectroscopy.

The skin acts mainly as a protective barrier from the external environment, thanks to the stratum corneum which is the outermost layer of the skin. As in vitro tests on skin are essential to elaborate new drugs, the development of skin models closer to reality becomes essential. It is now possible to produce in vitro human skin substitutes through tissue engineering by using the self-assembly method developed by the Laboratoire d'Organogénèse Expérimentale. In the present work, infrared microspectroscopy imaging analyses were performed to get in-depth morpho-spectral characterization of the three characteristic layers of human skin substitutes and normal human skin, namely the stratum corneum, living epidermis, and dermis. An infrared spectral analysis of the skin is a powerful tool to gain information on the order and conformation of the lipid chains and the secondary structure of proteins. On one hand, the symmetric stretching mode of the lipid methylene groups (2,850 cm(-1)) is sensitive to the acyl chain conformational order. The evolution profile of the frequency of this vibrational mode throughout the epidermis suggests that lipids in the stratum corneum are more ordered than those in the living epidermis. On the other hand, the frequencies of the infrared components underneath the envelop of the amide I band provide information about the overall protein conformation. The analysis of this mode establishes that the proteins essentially adopt an α-helix conformation in the epidermis, probably associated with the presence of keratin, while modifications of the protein content are observed in the dermis (extracellular matrix made of collagen). Finally, the lipid organization, as well as the protein composition in the different layers, is similar for human skin substitutes and normal human skin, confirming that the substitutes reproduce essential features of real skin and are appropriate biomimetics.

Promising new treatments for psoriasis.

Psoriasis is a chronic, proliferative, and inflammatory skin disease affecting 2-3% of the population and is characterized by red plaques with white scales. Psoriasis is a disease that can affect many aspects of professional and social life. Currently, several treatments are available to help control psoriasis such as methotrexate, ciclosporin, and oral retinoids. However, the available treatments are only able to relieve the symptoms and lives of individuals. The discovery of new immunological factors and a better understanding of psoriasis have turned to the use of immunological pathways and could develop new biological drugs against specific immunological elements that cause psoriasis. Biological drugs are less toxic to the body and more effective than traditional therapies. Thus, they should improve the quality of life of patients with psoriasis. This review describes new psoriasis treatments, which are on the market or currently in clinical trials that are being used to treat moderate-to-severe plaque psoriasis. In addition, this paper describes the characteristics and mechanisms in detail. In general, biological drugs are well tolerated and appear to be an effective alternative to conventional therapies. However, their effectiveness and long-term side effects need to be further researched.

The combination of cigarette smoke and solar rays causes effects similar to skin aging in a bilayer skin model.

Skin aging is a multifactorial process influenced by internal and external factors. The contribution of different environmental factors has been well established individually in the last few years. On the one hand, man is rarely exposed to a single factor, and on the other hand, there is very little knowledge about how these extrinsic factors may interact with each other or even how the skin may react to chronic exposure. This study aimed to evaluate the effect on skin aging of a chronic co-exposure of tissue-engineered skin substitutes to cigarette smoke extract (CSE) and solar simulator light (SSL). Skin substitutes were reconstructed according to the self-assembly method and then exposed to CSE followed by irradiation with SSL simultaneously transmitting UVA1, visible light and infrared. When skin substitutes were chronically exposed to CSE and SSL, a significant decrease in procollagen I synthesis and the inhibition of Smad2 phosphorylation of the TGF-ß signaling pathway were observed. A 6.7-fold increase in MMP-1 activity was also observed when CSE was combined with SSL, resulting in a decrease in collagen III and collagen IV protein expression. The secretory profile resulting from the toxic synergy was investigated and several alterations were observed, notably an increase in the quantities of pro-inflammatory cytokines. The results also revealed the activation of the ERK1/2 (3.4-fold) and JNK (3.3-fold) pathways. Taken together, the results showed that a synergy between the two environmental factors could provoke premature skin aging.

Toxic Interaction Between Solar Radiation and Cigarette Smoke on Primary Human Keratinocytes.

Solar radiation and cigarette smoke are two environmental risk factors known to affect skin integrity. Although the toxic effects of these factors on skin have been widely studied separately, few studies have focused on their interaction. The objective of this study was to evaluate and understand the synergistic harmful effects of cigarette smoke and solar rays on human primary keratinocytes. The keratinocytes were exposed to cigarette smoke extract (CSE) and then irradiated with a solar simulator light (SSL). The viability, as determined by measuring metabolic activity of skin cells, and the levels of global reactive oxygen species (ROS) were evaluated after exposure to CSE and SSL. The combination of 3% CSE with 29 kJ m-2 UVA caused a decrease of 81% in cell viability, while with 10% to 20% CSE, the cell viability was null. This phototoxicity was accompanied by an increase in singlet oxygen but a decrease in type I ROS when CSE and SSL were combined in vitro. Surprisingly, an increase in the CSE's total antioxidant capacity was also observed. These results suggest a synergy between the two environmental factors in their effect on skin cells, and more precisely a phototoxicity causing a drastic decrease in cell viability.

N-eicosapentaenoyl-ethanolamine decreases the proliferation of psoriatic keratinocytes in a reconstructed psoriatic skin model.

Psoriasis is an inflammatory skin disease that is characterized by keratinocyte hyperproliferation, abnormal epidermal differentiation and dysregulated lipid metabolism. Some lipid mediators of the N-acylethanolamines (NAEs) and monoacylglycerols (MAGs) can bind to cannabinoid (CB) receptors and are referred to as part of the endocannabinoidome. Their implication in psoriasis remains unknown. The aim of the present study was to characterize the endocannabinoid system and evaluate the effects of n-3-derived NAEs, namely N-eicosapentaenoyl-ethanolamine (EPEA), in psoriatic keratinocytes using a psoriatic skin model produced by tissue engineering, following the self-assembly method. Psoriatic skin substitutes had lower FAAH2 expression and higher MAGL, ABHD6 and ABHD12 expression compared with healthy skin substitutes. Treatments with alpha-linolenic acid (ALA) increased the levels of EPEA and 1/2-docosapentaenoyl-glycerol, showing that levels of n-3 polyunsaturated fatty acids modulate related NAE and MAG levels. Treatments of the psoriatic substitutes with 10 µM of EPEA for 7 days resulted in decreased epidermal thickness and number of Ki67 positive keratinocytes, both indicating decreased proliferation of psoriatic keratinocytes. EPEA effects on keratinocyte proliferation were inhibited by the CB1 receptor antagonist rimonabant. Exogenous EPEA also diminished some inflammatory features of psoriasis. In summary, n-3-derived NAEs can reduce the psoriatic phenotype of a reconstructed psoriatic skin model.

Eicosapentaenoic Acid Influences the Lipid Profile of an In Vitro Psoriatic Skin Model Produced with T Cells.

Psoriasis is a skin disease characterized by epidermal hyperplasia and an inappropriate activation of the adaptive immunity. A dysregulation of the skin's lipid mediators is reported in the disease with a predominance of the inflammatory cascade derived from n-6 polyunsaturated fatty acids (n-6 PUFAs). Bioactive lipid mediators derived from arachidonic acid (AA) are involved in the inflammatory functions of T cells in psoriasis, whereas n-3 PUFAs' derivatives are anti-inflammatory metabolites. Here, we sought to evaluate the influence of a supplementation of the culture media with eicosapentaenoic acid (EPA) on the lipid profile of a psoriatic skin model produced with polarized T cells. Healthy and psoriatic skin substitutes were produced following the auto-assembly technique. Psoriatic skin substitutes produced with or without T cells presented increased epidermal and dermal linolenic acid (LA) and AA levels. N-6 PUFA lipid mediators were strongly measured in psoriatic substitutes, namely, 13-hydroxyoctadecadienoic acid (13-HODE), prostaglandin E2 (PGE2) and 12-hydroxyeicosatetraenoic acid (12-HETE). The added EPA elevated the amounts of EPA, n-3 docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) in the epidermal and dermal phospholipids. The EPA supplementation balanced the production of epidermal lipid mediators, with an increase in prostaglandin E3 (PGE3), 12-hydroxyeicosapentaenoic acid (12-HEPE) and N-eicosapentaenoyl-ethanolamine (EPEA) levels. These findings show that EPA modulates the lipid composition of psoriatic skin substitutes by encouraging the return to a cutaneous homeostatic state.

Pathological crosstalk in vitro between T lymphocytes and lesional keratinocytes in psoriasis: necessity of direct cell-to-cell contact.

Psoriasis, a chronic autoimmune-related skin disease, involves both immune and non-immune cells like T cells and keratinocytes. This study investigates the regulatory role of T cells-keratinocyte interactions during psoriasis on immune factors production. Cytokines and chemokines were evaluated by multiplex and ELISA assays in an in vitro model of co-culture of keratinocytes with T lymphocytes. Keratinocytes were from psoriatic skin lesions or healthy skin. T lymphocytes were from healthy volunteers. Psoriatic keratinocytes (PKs) alone generated concentrations of tumor necrosis factor (TNF)-α, interleukin (IL)-6, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-1ß, IL-8, monocyte chemotactic protein (MCP)-1, interferon-γ-induced protein 10 kDa (IP-10) and vascular endothelial growth factor (VEGF) higher than those produced by healthy keratinocytes (HKs). In contrast, IL-1α and IL-Ra production was reduced in PKs. Normal T cells, which had no effect on HKs, increased the production of TNF-α, IL-6, GM-CSF, IL-8, MCP-1 and IP-10 by PKs, but did not influence PK production of IL-1ß, IL-1α, IL-Ra and VEGF. The most striking effects were obtained with PK- and IL-2-stimulated T lymphocytes: most of the above cytokines and chemokines were greatly upregulated, except IL-1ß and VEGF that were decreased or unchanged, respectively. In addition, fractalkine was overproduced in this latter condition only. Our results indicate (1) a functional interaction between keratinocytes and T lymphocytes that requires a direct cellular contact, and (2) a reciprocal influence that depends on cytokine and chemokine types. In conclusion, lesional keratinocytes from psoriasis vulgaris alter functions of normal T lymphocytes that conversely modulate these keratinocytes.

Current knowledge of the implication of lipid mediators in psoriasis.

The skin is an organ involved in several biological processes essential to the proper functioning of the organism. One of these essential biological functions of the skin is its barrier function, mediated notably by the lipids of the stratum corneum, and which prevents both penetration from external aggression, and transepidermal water loss. Bioactive lipid mediators derived from polyunsaturated fatty acids (PUFAs) constitute a complex bioactive lipid network greatly involved in skin homeostasis. Bioactive lipid mediators derived from n-3 and n-6 PUFAs have well-documented anti- and pro-inflammatory properties and are recognized as playing numerous and complex roles in the behavior of diverse skin diseases, including psoriasis. Psoriasis is an inflammatory autoimmune disease with many comorbidities and is associated with enhanced levels of pro-inflammatory lipid mediators. Studies have shown that a high intake of n-3 PUFAs can influence the development and progression of psoriasis, mainly by reducing the severity and frequency of psoriatic plaques. Herein, we provide an overview of the differential effects of n-3 and n-6 PUFA lipid mediators, including prostanoids, hydroxy-fatty acids, leukotrienes, specialized pro-resolving mediators, N-acylethanolamines, monoacylglycerols and endocannabinoids. This review summarizes current findings on lipid mediators playing a role in the skin and their potential as therapeutic targets for psoriatic patients.

Alpha-Linolenic Acid Modulates T Cell Incorporation in a 3D Tissue-Engineered Psoriatic Skin Model.

Psoriasis is an autoimmune skin disease with an increased number of leukocytes infiltrating the dermal and epidermal compartments compared with normal skin. N-3 polyunsaturated fatty acids (n-3 PUFAs) are frequently used in the clinic in order to attenuate the symptoms of psoriasis. For psoriatic patients, a supplementation of the diet with alpha-linolenic acid (ALA) reduces the activation of T cell signaling pathways, leading to a significant reduction in inflammatory cytokine secretion. However, the precise mechanism of action of n-3 PUFAs in psoriasis is still not understood. In the present study, we elucidated the bioaction of ALA on the adaptive immune component of psoriasis by using a psoriatic skin model produced with the addition of activated T cells. Healthy and psoriatic skin substitutes were produced according to the self-assembly method, using culture media supplemented with 10 µM of ALA. T cells were isolated from blood samples using a negative selection isolation method. ALA supplementation regulated the hyperproliferation and abnormal cell differentiation of psoriatic keratinocytes stimulated by T cells. Additionally, the exogenous ALA was correctly incorporated into the phospholipids of keratinocytes, which resulted in increased levels of ALA, eicosapentaenoic acid (EPA) and n-3 docosapentaenoic acid (n-3 DPA). The infiltration of T cells into the epidermis was reduced when ALA was added to the culture medium, and significant decreases in the levels of inflammatory cytokines and chemokines such as CXCL1, interleukin-6 (IL-6) and interleukin-8 (IL-8) were consequently measured in psoriatic substitutes supplemented with this n-3 PUFA. Altogether, our results showed that in this psoriatic skin model enriched with T cells, ALA exerted its beneficial effect by decreasing the quantities of inflammatory mediators released by T cells.