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

Morin, Sophie / Simard, Mélissa / Rioux, Geneviève / Julien, Pierre / Pouliot, Roxane

2022 Volume 11, Issue 9

Abstract: 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 ... ...

Abstract	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.
MeSH term(s)	Fatty Acids, Omega-3/pharmacology ; Humans ; Keratinocytes/metabolism ; Psoriasis/metabolism ; Skin/metabolism ; T-Lymphocytes/metabolism ; alpha-Linolenic Acid/pharmacology
Chemical Substances	Fatty Acids, Omega-3 ; alpha-Linolenic Acid (0RBV727H71)
Language	English
Publishing date	2022-04-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11091513
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Article ; Online: N-eicosapentaenoyl-ethanolamine decreases the proliferation of psoriatic keratinocytes in a reconstructed psoriatic skin model.

Simard, Mélissa / Tremblay, Andréa / Morin, Sophie / Rioux, Geneviève / Flamand, Nicolas / Pouliot, Roxane

Scientific reports

2023 Volume 13, Issue 1, Page(s) 12113

Abstract: 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) ... ...

Abstract	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 CB
MeSH term(s)	Humans ; Ethanolamine/metabolism ; Skin/metabolism ; Keratinocytes/metabolism ; Psoriasis/drug therapy ; Psoriasis/metabolism ; Cell Proliferation ; Ethanolamines/pharmacology ; Ethanolamines/metabolism ; Monoacylglycerol Lipases/metabolism
Chemical Substances	Ethanolamine (5KV86114PT) ; N-acylethanolamines ; Ethanolamines ; ABHD12 protein, human (EC 3.1.1.23) ; Monoacylglycerol Lipases (EC 3.1.1.23)
Language	English
Publishing date	2023-07-26
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-023-39185-4
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Article ; Online: Gene Profiling of a 3D Psoriatic Skin Model Enriched in T Cells: Downregulation of

Rioux, Geneviève / Turgeon, Florence / Le-Bel, Gaëtan / Grenier, Camille / Guérin, Sylvain L / Pouliot, Roxane

Cells

2022 Volume 11, Issue 18

Abstract: Psoriasis is a complex, immune-mediated skin disease involving a wide range of epithelial and immune cells. The underlying mechanisms that govern the epidermal defects and immunological dysfunction observed in this condition remain largely unknown. In ... ...

Abstract	Psoriasis is a complex, immune-mediated skin disease involving a wide range of epithelial and immune cells. The underlying mechanisms that govern the epidermal defects and immunological dysfunction observed in this condition remain largely unknown. In recent years, the emergence of new, more sophisticated models has allowed the evolution of our knowledge of the pathogenesis of psoriasis. The development of psoriatic skin biomaterials that more closely mimic native psoriatic skin provides advanced preclinical models that will prove relevant in predicting clinical outcomes. In this study, we used a tissue-engineered, two-layered (dermis and epidermis) human skin substitute enriched in T cells as a biomaterial to study both the cellular and molecular mechanisms involved in psoriasis' pathogenesis. Gene profiling on microarrays revealed significant changes in the profile of genes expressed by the psoriatic skin substitutes compared with the healthy ones. Two genes, namely,
MeSH term(s)	Antigen-Antibody Complex/analysis ; Antigen-Antibody Complex/genetics ; Antigen-Antibody Complex/metabolism ; Biocompatible Materials/therapeutic use ; Cell Proliferation/genetics ; DNA/metabolism ; Down-Regulation ; Humans ; Keratinocytes/metabolism ; MAP Kinase Signaling System ; NF-kappa B/metabolism ; Psoriasis/drug therapy ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/analysis ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/genetics ; Receptor-Like Protein Tyrosine Phosphatases, Class 2/metabolism ; Signal Transduction ; T-Lymphocytes
Chemical Substances	Antigen-Antibody Complex ; Biocompatible Materials ; NF-kappa B ; DNA (9007-49-2) ; PTPRM protein, human (EC 3.1.3.48) ; Receptor-Like Protein Tyrosine Phosphatases, Class 2 (EC 3.1.3.48)
Language	English
Publishing date	2022-09-16
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells11182904
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Article: Remodeling of the Dermal Extracellular Matrix in a Tissue-Engineered Psoriatic Skin Model by n-3 Polyunsaturated Fatty Acids.

Simard, Mélissa / Grenier, Alexe / Rioux, Geneviève / Tremblay, Andréa / Blais, Isalie / Flamand, Nicolas / Pouliot, Roxane

Biomedicines

2022 Volume 10, Issue 5

Abstract: Psoriasis is an inflammatory skin disease mainly associated with an epidermal disorder. However, the involvement of the dermal extracellular matrix (ECM) composition in psoriasis is still poorly understood. This study aimed to investigate the expression ... ...

Abstract	Psoriasis is an inflammatory skin disease mainly associated with an epidermal disorder. However, the involvement of the dermal extracellular matrix (ECM) composition in psoriasis is still poorly understood. This study aimed to investigate the expression of ECM components in psoriatic skin substitutes (PS
Language	English
Publishing date	2022-05-06
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2720867-9
ISSN	2227-9059
ISSN	2227-9059
DOI	10.3390/biomedicines10051078
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Article ; Online: Development of a 3D psoriatic skin model optimized for infiltration of IL-17A producing T cells: Focus on the crosstalk between T cells and psoriatic keratinocytes.

Rioux, Geneviève / Simard, Mélissa / Morin, Sophie / Lorthois, Isabelle / Guérin, Sylvain L / Pouliot, Roxane

Acta biomaterialia

2021 Volume 136, Page(s) 210–222

Abstract: Psoriasis is a chronic inflammatory skin disease involving several cell types, including T cells, via the IL-23/IL-17 axis. IL-17A acts on the surrounding epithelial cells thus resulting in an inflammatory feedback loop. The development of ... ...

Abstract	Psoriasis is a chronic inflammatory skin disease involving several cell types, including T cells, via the IL-23/IL-17 axis. IL-17A acts on the surrounding epithelial cells thus resulting in an inflammatory feedback loop. The development of immunocompetent models that correctly recapitulate the complex phenotype of psoriasis remains challenging, which also includes both the T cell isolation and activation methods. The purpose of this work was to develop an advanced in vitro 3D psoriatic skin model that enables the study of the impact of T cells on psoriatic epithelial cells. To reach that aim, healthy and psoriatic fibroblasts and keratinocytes were used to reproduce this tissue-engineered skin model in which activated T cells, isolated beforehand from human whole blood, have been incorporated. Our study showed that isolation of T cells with the EasySep procedure, followed by activation with PMA/ionomycin, mimicked the psoriatic characteristics in an optimal manner with the production of inflammatory cytokines important in the pathogenesis of psoriasis, as well as increased expression of Ki67, S100A7, elafin and involucrin. This psoriatic model enriched in activated T cells displayed enhanced production of IL-17A, IFN-ƴ, CCL2, CXCL10, IL-1ra, IL-6 and CXCL8 compared with the healthy model and whose increased secretion was maintained over time. In addition, anti-IL17A treatment restored some psoriatic features, including epidermal thickness and basal keratinocytes proliferation, as well as a downregulation of S100A7, elafin and involucrin expression. Altogether, our study demonstrated that this model reflects a proper psoriatic inflammatory environment and is effective for the investigation of epidermal and T cell interaction over time. STATEMENT OF SIGNIFICANCE: The aim of this study was to provide an innovative 3D immunocompetent human psoriatic skin model. To our knowledge, this is the first immunocompetent model that uses skin cells from psoriatic patients to study the impact of IL-17A on pathological cells. Through the use of this model, we demonstrated that the T-cell enriched psoriatic model differs from T-cell enriched healthy model, highlighting efficient crosstalk between pathologic epithelial cells and T cells. This advanced preclinical model further mimics the original psoriatic skin and will prove relevant in predicting clinical outcomes, thereby decreasing inaccurate predictions of compound effects.
MeSH term(s)	Cell Culture Techniques, Three Dimensional/methods ; Humans ; Interleukin-17 ; Keratinocytes/cytology ; Psoriasis/immunology ; Skin ; T-Lymphocytes/cytology
Chemical Substances	Interleukin-17
Language	English
Publishing date	2021-09-20
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2173841-5
ISSN	1878-7568 ; 1742-7061
ISSN (online)	1878-7568
ISSN	1742-7061
DOI	10.1016/j.actbio.2021.09.018
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Article: Transcriptome Profiling Analyses in Psoriasis: A Dynamic Contribution of Keratinocytes to the Pathogenesis

Rioux, Geneviève / Ridha, Zainab / Simard, Mélissa / Turgeon, Florence / Guérin, Sylvain L / Pouliot, Roxane

Genes. 2020 Sept. 30, v. 11, no. 10

2020

Abstract: Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. A better insight into related genomic alteration helps design precise therapies leading to better treatment outcome. Gene ... ...

Abstract	Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. A better insight into related genomic alteration helps design precise therapies leading to better treatment outcome. Gene expression in psoriasis can provide relevant information about the altered expression of mRNA transcripts, thus giving new insights into the disease onset. Techniques for transcriptome analyses, such as microarray and RNA sequencing (RNA-seq), are relevant tools for the discovery of new biomarkers as well as new therapeutic targets. This review summarizes the findings related to the contribution of keratinocytes in the pathogenesis of psoriasis by an in-depth review of studies that have examined psoriatic transcriptomes in the past years. It also provides valuable information on reconstructed 3D psoriatic skin models using cells isolated from psoriatic patients for transcriptomic studies.
Keywords	biomarkers ; etiology ; gene expression ; genomics ; keratinocytes ; microarray technology ; pathogenesis ; psoriasis ; sequence analysis ; therapeutics ; transcriptome ; transcriptomics
Language	English
Dates of publication	2020-0930
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article
ZDB-ID	2527218-4
ISSN	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11101155
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Transcriptome Profiling Analyses in Psoriasis: A Dynamic Contribution of Keratinocytes to the Pathogenesis.

Rioux, Geneviève / Ridha, Zainab / Simard, Mélissa / Turgeon, Florence / Guérin, Sylvain L / Pouliot, Roxane

Genes

2020 Volume 11, Issue 10

Abstract	Psoriasis is an immune-mediated inflammatory skin disease with a complex etiology involving environmental and genetic factors. A better insight into related genomic alteration helps design precise therapies leading to better treatment outcome. Gene expression in psoriasis can provide relevant information about the altered expression of mRNA transcripts, thus giving new insights into the disease onset. Techniques for transcriptome analyses, such as microarray and RNA sequencing (RNA-seq), are relevant tools for the discovery of new biomarkers as well as new therapeutic targets. This review summarizes the findings related to the contribution of keratinocytes in the pathogenesis of psoriasis by an in-depth review of studies that have examined psoriatic transcriptomes in the past years. It also provides valuable information on reconstructed 3D psoriatic skin models using cells isolated from psoriatic patients for transcriptomic studies.
MeSH term(s)	Cells, Cultured ; Female ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; Immunity/genetics ; In Vitro Techniques ; Keratinocytes/physiology ; Lipid Metabolism ; Lipids ; Male ; Psoriasis/genetics ; Psoriasis/pathology ; Psoriasis/physiopathology ; Transcriptome
Chemical Substances	Lipids
Language	English
Publishing date	2020-09-30
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2527218-4
ISSN	2073-4425 ; 2073-4425
ISSN (online)	2073-4425
ISSN	2073-4425
DOI	10.3390/genes11101155
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Article ; Online: 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.

Simard, Mélissa / Morin, Sophie / Rioux, Geneviève / Séguin, Rachelle / Loing, Estelle / Pouliot, Roxane

International journal of molecular sciences

2020 Volume 21, Issue 15

Abstract: 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. ... ...

Abstract	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
MeSH term(s)	Adenylyl Cyclases/metabolism ; Cholera Toxin/toxicity ; Cyclic AMP/metabolism ; Epidermis/metabolism ; Epidermis/pathology ; Female ; Humans ; Isoproterenol/administration & dosage ; Isoproterenol/pharmacology ; Male ; Middle Aged ; Models, Biological ; Psoriasis/metabolism ; Psoriasis/pathology ; Second Messenger Systems/drug effects ; Tissue Engineering
Chemical Substances	Cholera Toxin (9012-63-9) ; Cyclic AMP (E0399OZS9N) ; Adenylyl Cyclases (EC 4.6.1.1) ; adenylate cyclase 9 (EC 4.6.1.1) ; Isoproterenol (L628TT009W)
Language	English
Publishing date	2020-07-23
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms21155215
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Article ; Online: Investigation of Omega-3 Polyunsaturated Fatty Acid Biological Activity in a Tissue-Engineered Skin Model Involving Psoriatic Cells.

Simard, Mélissa / Rioux, Geneviève / Morin, Sophie / Martin, Cyril / Guérin, Sylvain L / Flamand, Nicolas / Julien, Pierre / Fradette, Julie / Pouliot, Roxane

The Journal of investigative dermatology

2021 Volume 141, Issue 10, Page(s) 2391–2401.e13

Abstract: Clinical studies have shown that diets enriched with omega-3 (also know as n-3) polyunsaturated fatty acids could relieve the symptoms of patients with psoriasis. However, the mechanisms involved remain poorly understood. The aim of this study was to ... ...

Abstract	Clinical studies have shown that diets enriched with omega-3 (also know as n-3) polyunsaturated fatty acids could relieve the symptoms of patients with psoriasis. However, the mechanisms involved remain poorly understood. The aim of this study was to investigate the effects of α-linolenic acid (ALA) on the proliferation and differentiation of psoriatic keratinocytes in a three-dimensional skin model. Skin models featuring healthy (healthy substitute) or psoriatic (psoriatic substitute) cells were engineered by the self-assembly method of tissue engineering using a culture medium supplemented with 10 μM ALA in comparison with the regular unsupplemented medium. ALA decreased keratinocyte proliferation and improved psoriatic substitute epidermal differentiation, as measured by decreased Ki67 staining and increased protein expression of FLG and loricrin. The added ALA was notably incorporated into the epidermal phospholipids and metabolized into long-chain n-3 polyunsaturated fatty acids, mainly eicosapentaenoic acid and n-3 docosapentaenoic acid. ALA supplementation led to increased levels of eicosapentaenoic acid derivatives (15-hydroxyeicosapentaenoic acid and 18-hydroxyeicosapentaenoic acid) as well as a decrease in levels of omega-6 (also know as n-6) polyunsaturated fatty acid lipid mediators (9-hydroxyoctadecadienoic acid, 12-hydroxyeicosatetraenoic acid, and leukotriene B
MeSH term(s)	12-Hydroxy-5,8,10,14-eicosatetraenoic Acid/analysis ; Cell Differentiation/drug effects ; Cell Proliferation/drug effects ; Dietary Supplements ; Extracellular Signal-Regulated MAP Kinases/physiology ; Humans ; Keratinocytes/drug effects ; Keratinocytes/pathology ; Leukotriene B4/analysis ; Psoriasis/drug therapy ; Psoriasis/metabolism ; Psoriasis/pathology ; Tissue Engineering ; alpha-Linolenic Acid/administration & dosage ; alpha-Linolenic Acid/pharmacology
Chemical Substances	alpha-Linolenic Acid (0RBV727H71) ; Leukotriene B4 (1HGW4DR56D) ; 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid (59985-28-3) ; Extracellular Signal-Regulated MAP Kinases (EC 2.7.11.24)
Language	English
Publishing date	2021-04-20
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80136-7
ISSN	1523-1747 ; 0022-202X
ISSN (online)	1523-1747
ISSN	0022-202X
DOI	10.1016/j.jid.2021.02.755
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Article ; Online: Synthesis and Properties of Rhomboidal Macrocyclic Subunits of Graphdiyne-Like Nanoribbons.

Desroches, Maude / Courtemanche, Marc-André / Rioux, Geneviève / Morin, Jean-François

The Journal of organic chemistry

2015 Volume 80, Issue 21, Page(s) 10634–10642

Abstract: Rhomboidal macrocyclic subunits of graphdiyne-like nanoribbon (GDNR) bearing both alkyne and diyne units, allowing for multichannel π-conjugation, were synthesized using an oxidative Glaser-type ring closing reaction. These subunits, called the "meshes" ... ...

Abstract	Rhomboidal macrocyclic subunits of graphdiyne-like nanoribbon (GDNR) bearing both alkyne and diyne units, allowing for multichannel π-conjugation, were synthesized using an oxidative Glaser-type ring closing reaction. These subunits, called the "meshes" of the nanoribbon, possess phenyl groups with decyloxy solubilizing chains on each corner. The yields of the ring closing reaction highly depend on the metal (Cu or Pd) catalyst used for the macrocyclization step. Increasing the width of the meshes from one macrocycle to two fused macrocycles resulted in a decrease of the bandgap by 0.23 eV as shown by optical spectroscopy. The optimized geometries of the meshes alongside their HOMO and LUMO orbitals were calculated using DFT calculations at the B3LYP/6-31+G** level of theory. The results showed a nearly planar conformation for both meshes with HOMO and LUMO orbitals entirely delocalized over the molecules.
Language	English
Publishing date	2015-11-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	123490-0
ISSN	1520-6904 ; 0022-3263
ISSN (online)	1520-6904
ISSN	0022-3263
DOI	10.1021/acs.joc.5b01752
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