Psoriasis-associated impairment of CCL27/CCR10-derived regulation leads to IL-17A/IL-22-producing skin T-cell overactivation.
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ABSTRACT:
SUBMITTER: Li C
PROVIDER: S-EPMC7726097 | biostudies-literature |
REPOSITORIES: biostudies-literature
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| S-EPMC5921865 | biostudies-literature
Project description:Human gammadelta T cells expressing the Vgamma2Vdelta2 TCR play important roles in immune responses to microbial pathogens by monitoring prenyl pyrophosphate isoprenoid metabolites. Most adult Vgamma2Vdelta2 cells are memory cytotoxic cells that produce IFN-gamma. Recently, murine gammadelta T cells were found to be major sources of IL-17A in antimicrobial and autoimmune responses. To determine if primate gammadelta T cells play similar roles, we characterized IL-17A and IL-22 production by Vgamma2Vdelta2 cells. IL-17A-producing memory Vgamma2Vdelta2 cells exist at low but significant frequencies in adult humans (1:2762 T cells) and at even higher frequencies in adult rhesus macaques. Higher levels of Vgamma2Vdelta2 cells produce IL-22 (1:1864 T cells), although few produce both IL-17A and IL-22. Unlike adult humans, in whom many IL-17A+ Vgamma2Vdelta2 cells also produce IFN-gamma (Tgammadelta1/17), the majority of adult macaques IL-17A+ Vdelta2 cells (Tgammadelta17) do not produce IFN-gamma. To define the cytokine requirements for Tgammadelta17 cells, we stimulated human neonatal Vgamma2Vdelta2 cells with the bacterial Ag, (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate, and various cytokines and mAbs in vitro. We find that IL-6, IL-1beta, and TGF-beta are required to generate Tgammadelta17 cells in neonates, whereas Tgammadelta1/17 cells additionally required IL-23. In adults, memory Tgammadelta1/17 and Tgammadelta17 cells required IL-23, IL-1beta, and TGF-beta, but not IL-6. IL-22-producing cells showed similar requirements. Both neonatal and adult IL-17A+ Vgamma2Vdelta2 cells expressed elevated levels of retinoid-related orphan receptor gammat. Our data suggest that, like Th17 alphabeta T cells, Vgamma2Vdelta2 T cells can be polarized into Tgammadelta17 and Tgammadelta1/17 populations with distinct cytokine requirements for their initial polarization and later maintenance.
| S-EPMC2965829 | biostudies-literature
Project description:The present paradigm of psoriasis pathogenesis revolves around the IL-23/IL-17A axis. Dual-secreting Th17 T cells presumably are the predominant sources of the psoriasis phenotype-driving cytokines, IL-17A and IL-22. We thus conducted a meta-analysis of independently acquired RNA-seq psoriasis datasets to explore the relationship between the expression of IL17A and IL22. This analysis failed to support the existence of dual secreting IL-17A/IL-22 Th17 cells as a major source of these cytokines. However, variable relationships amongst the expression of psoriasis susceptibility genes and of IL17A, IL22, and IL23A were identified. Additionally, to shed light on gene expression relationships in psoriasis, we applied a machine learning nonlinear dimensionality reduction strategy (t-SNE) to display the entire psoriasis transcriptome as a 2-dimensonal image. This analysis revealed a variety of gene clusters, relevant to psoriasis pathophysiology but failed to support a relationship between IL17A and IL22. These results support existing theories on alternative sources of IL-17A and IL-22 in psoriasis such as a Th22 cells and non-T cell populations.
| S-EPMC6458264 | biostudies-literature
Project description:The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients. In addition, chemokine levels were significantly higher in samples from patients who became refractory to bortezomib at first line treatment compared to resistance at later treatment lines.In vitro as well as in an in vivo model we could show that CCL27 triggers bortezomib-resistance of myeloma cells. This effect was strictly dependent on the expression of the respective receptor, CCR10, on stroma cells and involved the modulation of IL-10 expression, activation of myeloma survival pathways, and modulation of proteasomal activity. Drug resistance could be totally reversed by blocking CCR10 by siRNA as well as blocking IL-10 and its receptor.From our data we suggest that blocking the CCR10/CCL27/IL-10 myeloma-stroma crosstalk is a novel therapeutic target that could be especially relevant in early refractory myeloma patients.
| S-EPMC5346663 | biostudies-literature
Project description:Plaque psoriasis is an autoinflammatory and autoimmune skin disease, affecting 1-3% of the population worldwide. Previously, high levels of IL-36 family cytokines were found in psoriatic skin lesions, thereby contributing to keratinocyte hyperproliferation and infiltration of immune cells such as neutrophils. While treatment with anti-IL36 receptor (IL36R) antibodies was recently approved for generalized pustular psoriasis (GPP), it remains unclear, if targeting the IL36R might also inhibit plaque psoriasis. Here we show that antibody-mediated inhibition of IL36R is sufficient to suppress imiquimod-induced psoriasis-like skin inflammation and represses the disease's development in a model that depends on IL-17A overexpression in the skin. Importantly, treatment with anti-IL36R antibodies inhibited skin inflammation and attenuated psoriasis-associated, systemic inflammation. This is possibly due to a widespread effect of IL36R inhibition, which not only suppresses pro-inflammatory gene expression in keratinocytes, but also the activation of other immune cells such as T-cells or dendritic cells. In conclusion, we propose that inhibition of the IL-36 signaling pathway might constitute an attractive, alternative approach for treating IL-17A-driven psoriasis and psoriasis-linked comorbidities.
| S-EPMC10754973 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2023-11-20 | GSE189232 | GEO
Project description:BackgroundPsoriasis is a chronic immune-mediated skin condition. Although biologic treatments are effective in controlling psoriasis, some patients do not respond or lose response to these therapies. Thus, new strategies for psoriasis treatment are still urgently needed. Double-negative T cells (DNT) play a significant immunoregulatory role in autoimmune diseases. In this study, we aimed to evaluate the protective effect of DNT in psoriasis and explore the underlying mechanism.MethodsWe conducted a single adoptive transfer of DNT into an imiquimod (IMQ)-induced psoriasis mouse model through tail vein injection. The skin inflammation and IL-17A producing γδ T cells were evaluated.ResultsDNT administration significantly reduced the inflammatory response in mouse skin, characterized by decreased skin folds, scales, and red patches. After DNT treatment, the secretion of IL-17A by RORc+ γδlow T cells in the skin was selectively suppressed, resulting in an amelioration of skin inflammation. Transcriptomic data suggested heightened expression of NKG2D ligands in γδlow T cells within the mouse model of psoriasis induced by IMQ. When blocking the NKG2D ligand and NKG2D (expressed by DNT) interaction, the cytotoxic efficacy of DNT against RORc+IL17A+ γδlow T cells was attenuated. Using Ccr5-/- DNT for treatment yielded evidence that DNT migrates into inflamed skin tissue and fails to protect IMQ-induced skin lesions.ConclusionsDNT could migrate to inflamed skin tissue through CCR5, selectively inhibit IL-17-producing γδlow T cells and finally ameliorate mouse psoriasis. Our study provides feasibility for using immune cell therapy for the prevention and treatment of psoriasis in the clinic.
| S-EPMC10988838 | biostudies-literature
Project description:Psoriasis is a chronic inflammatory skin disease characterized by Th17 responses. Recent evidence has identified Langerhans cells to have a key role in disease pathogenesis, with constitutive high expression of CD1a and capacity to present lipid antigens to T cells. Phospholipase A2 enzymes generate neolipid antigens for recognition by CD1a-reactive T cells; however, the broader enzymatic pathways of CD1a lipid ligand generation have not been thoroughly investigated. In this study, we used immunofluorescence of skin and ELISpot analyses of CD1a-reactive T cells to investigate the role of the lipase acyloxyacyl hydrolase (AOAH) in CD1a ligand generation with relevance to the pathogenesis of psoriasis. We found that the PLA2 activity of rAOAH leads to the activation of circulating CD1a auto-reactive T cells, leading to the production of IFN-γ and IL-22. Circulating AOAH-responsive CD1a-reactive T cells from patients with psoriasis showed elevated IL-22 production. We observed that AOAH is highly expressed in psoriatic lesions compared to healthy skin. Overall, these data present a role for AOAH in generating antigens that activate circulating lipid-specific CD1a-restricted T cells and, thus, contribute to psoriatic inflammation. These findings suggest that inhibition of PLA2 activity of AOAH may have therapeutic potential for individuals with psoriasis.
| S-EPMC9302981 | biostudies-literature
Project description:Psoriasis is a frequent chronic inflammatory skin disease, nowadays considered a major global health problem. Several new drugs, targeting the IL-23/IL-17A pathway, have been recently licensed or are in clinical development. These therapies represent a major improvement of the way in which psoriasis is managed, since they show an unprecedented efficacy on skin symptoms of psoriasis. This has been made possible, thanks to an increasingly more accurate pathogenic view of psoriasis. Today, the belief that Th17?cells mediate psoriasis is moving to the concept of psoriasis as an IL-17A-driven disease. New questions arise at the horizon, given that IL-17A is part of a newly described family of cytokines, which has five distinct homologous: IL-17B, IL-17C, IL-17D, IL-17E, also known as IL-25 and IL-17F. IL-17 family cytokines elicit similar effects in target cells, but simultaneously trigger different and sometimes opposite functions in a tissue-specific manner. This is complicated by the fact that IL-17 cytokines show a high capacity of synergisms with other inflammatory stimuli. In this review, we will summarize the current knowledge around the cytokines belonging to the IL-17 family in relation to skin inflammation in general and psoriasis in particular, and discuss possible clinical implications. A comprehensive understanding of the different roles played by the IL-17 cytokines is crucial to appreciate current and developing therapies and to allow an effective pathogenesis- and mechanisms-driven drug design.
| S-EPMC6088173 | biostudies-literature
Project description:BackgroundPsoriasis and atopic dermatitis (AD) are common inflammatory skin diseases. An upregulated TH17/IL-23 pathway was demonstrated in psoriasis. Although potential involvement of TH17 T cells in AD was suggested during acute disease, the role of these cells in chronic AD remains unclear.ObjectiveTo examine differences in IL-23/TH17 signal between these diseases and establish relative frequencies of T-cell subsets in AD.MethodsSkin biopsies and peripheral blood were collected from patients with chronic AD (n = 12) and psoriasis (n = 13). Relative frequencies of CD4+ and CD8+ T-cell subsets within these 2 compartments were examined by intracellular cytokine staining and flow cytometry.ResultsIn peripheral blood, no significant difference was found in percentages of different T-cell subsets between these diseases. In contrast, psoriatic skin had significantly increased frequencies of TH1 and TH17 T cells compared with AD, whereas TH2 T cells were significantly elevated in AD. Distinct IL-22-producing CD4+ and CD8+ T-cell populations were significantly increased in AD skin compared with psoriasis. IL-22+CD8+ T-cell frequency correlated with AD disease severity.ConclusionOur data established that T cells could independently express IL-22 even with low expression levels of IL-17. This argues for a functional specialization of T cells such that "T17" and "T22" T-cells may drive different features of epidermal pathology in inflammatory skin diseases, including induction of antimicrobial peptides for "T17" T cells and epidermal hyperplasia for "T22" T-cells. Given the clinical correlation with disease severity, further characterization of "T22" T cells is warranted, and may have future therapeutic implications.
| S-EPMC2874584 | biostudies-literature