Molecular improvement of IL-23 inhibition revealed by single-cell RNA sequencing in concurrent psoriasis and systemic lupus erythematosus
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE299258 | GEO | 2026/01/20
REPOSITORIES: GEO
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Project description:Recent single-cell studies indicated that IL-17-producing T-cells (T17) have diverse subsets expressing IL-17A, IL-17F, or a combination of them in human psoriasis skin. However, it is unknown how T17 subsets are differently regulated by IL-23 versus IL-17A blockades. Here, we studied 93 human psoriasis or control skin single-cell libraries from 42 subjects to understand how IL-23 versus IL-17A systemic blockades differently modify single-cell transcriptome of T17 cell subsets, dendritic cells/myeloid cells, and keratinocytes. Our study shows that IL-23 inhibition down-regulates IL-23 receptor-expressing pathogenic T17 subsets. In contrast, T17 cells expressing both IL-17A and IL-17F did not express the IL-23 receptor, and the percentage of this potentially non-pathogenic T17 subset increased after IL-23 inhibition. We also found out that the expression of the IL-17 negative regulation genes, such as TNFAIP3, increased in myeloid cells more after IL-23 inhibition than after IL-17A inhibition. These findings explain why the risk of candidiasis is not increased after IL-23 inhibition, unlike IL-17 inhibition, and the higher efficacy of IL-23 blockades for inducing psoriasis remission in the long term or suppressing relapses after stopping the injections compared to IL-17A blockades.
2025-02-18 | GSE278330 | GEO
Project description:Background: Based on the mounting evidence that Type 17 T-cells (T17 cells) and increased IL-17 play a key role in driving hidradenitis suppurativa (HS) lesion development, biologics previously used in psoriasis that block signaling of IL-17A and/or IL-17F isoforms have been repurposed to treat HS. Objective: Our aim was to characterize the transcriptome of HS T17 cells compared to the transcriptome of psoriasis T17 cells, and their ligand-receptor interactions with neighborhood immune cell subsets. Methods: Single-cell data of 12,300 cutaneous immune cells from 8 de-roofing surgical HS skin samples that included dermal tunnels were compared with single-cell data of psoriasis skin (19,525 cells from 11 samples) and control skin (11,920 cells from 10 samples). All the single-cell data were generated by the identical protocol. Results: HS T17 cells expressed lower levels of IL23R and higher levels of IL1R1 and IL17F compared to psoriasis T17 cells (p < 0.05). HS regulatory T-cells (Tregs) expressed higher levels of IL1R1 and IL17F compared to psoriasis Tregs (p < 0.05). Semimature dendritic cells (DCs) were the major immune cell subsets expressing IL1B in HS, and IL-1B ligand-receptor interactions between semimature DCs and T17 cells were increased in HS compared to psoriasis (p < 0.05). HS dermal tunnel keratinocytes (KCs) expressed inflammatory cytokines (IL17C, IL1A, IL1B, and IL6) different from HS epidermis KCs (IL36G) (p < 0.05). IL6, which synergizes with IL1B to maintain cytokine expression in T17 cells, was mainly expressed by fibroblasts in HS, which also expressed IL11+ inflammatory fibroblast genes (IL11, IL24, IL6, and POSTN) involved in paracrine IL-1/IL-6 loop. Conclusion: The IL-1B-T17 cell cytokine axis is likely a dominant pathway in HS with HS T17 cells activated by IL-1B signaling, unlike psoriasis T17 cells which are activated by IL-23 signaling. Clinical Implication: Biologics targeting IL-17 isoforms and IL-1B may be effective for HS but biologics targeting IL-23 may be less effective for HS.
2023-06-02 | GSE220116 | GEO
Project description:Durable psoriasis improvement has been reported in a subset of psoriasis patients after treatment withdrawal of biologics blocking IL-23/Type 17 T-cell (T17) autoimmune axis. However, it is not well understood if systemic blockade of the IL-23/T17 axis promotes immune tolerance in psoriasis skin. The purpose of the study was to find translational evidence that systemic IL-17A blockade promotes regulatory transcriptome modification in human psoriasis skin immune cell subsets. We analyzed human psoriasis lesional skin 6 mm punch biopsy tissues before and after systemic IL-17A blockade using the muti-genomics approach integrating immune cell-enriched scRNA-seq (n = 18), microarray (n = 61), and immunohistochemistry (n = 61) with repository normal control skin immune cell-enriched scRNA-seq (n = 10) and microarray (n = 8) data. For the T17 axis transcriptome, systemic IL-17A blockade depleted 100% of IL17A + T-cells and 95% of IL17F + T-cells in psoriasis skin. The expression of IL23A in DC subsets was also downregulated by IL-17A blockade. The expression of IL-17-driven inflammatory mediators (IL36G, S100A8, DEFB4A, and DEFB4B) in suprabasal keratinocytes was correlated with psoriasis severity and was downregulated by IL-17A blockade. For the regulatory DC transcriptome, the proportion of regulatory semimature DCs expressing regulatory DC markers of BDCA-3 (THBD) and DCIR (CLEC4A) was increased in posttreatment psoriasis lesional skin compared to pretreatment psoriasis lesional skin. In addition, IL-17A blockade induced higher expression of CD1C and CD14, which are markers of CD1c+ CD14+ dendritic cell (DC) subset that suppresses antigen-specific T-cell responses, in posttreatment regulatory semimature DCs compared to pretreatment regulatory semimature DCs. In conclusion, systemic IL-17A inhibition not only blocks the entire IL-23/T17 cell axis but also promotes regulatory gene expression in regulatory DCs in human psoriasis skin.
2023-09-04 | GSE183047 | GEO
Project description:Background and Purpose: The chemokine receptor CCR6 is important in guiding pathogenic T17 cells that are implicated in numerous autoimmune diseases including psoriasis to sites of inflammation via the chemokine CCL20. On this basis, pharmacological interventions that inhibit CCR6+ immune cell migration provide a novel therapeutic approach for such diseases. However, the translatability from pre-clinical models to human diseases of such an intervention has so far not been assessed in detail. Here, we evaluate the translatability of a preclinical model of Aldara induced skin inflammation to psoriasis with a particular focus on immune cell trafficking and assess the efficacy of the novel, orally available CCR6 antagonist IDOR-1117-2520 in this model. Experimental Approach: Here, we evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. To understand in detail CCR6 inhibition on the inflammatory response, flow cytometry, RNA sequencing, and transcriptome-based cell type deconvolution approaches were used to characterize immune cell migration patterns and to compare the results to publicly available human psoriasis transcriptomics data. Key Results: IDOR-1117-2520 dose dependently reduced infiltration of CCR6 + immune cells into inflamed skin and was equally efficacious as IL-17 and IL-23 inhibition in reducing inflammation in the skin. Pathway analysis highlighted the strong molecular similarities in immune response between human psoriasis and the Aldara mouse model. Genes associated with the IL-17/IL-23 pathway were prominently expressed in both human psoriasis and in the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated the CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in this model system, as well as in human psoriasis. Conclusion and Implications: These results suggest that IDOR-1117-2520 could provide a promising novel targeted therapeutic approach to treating psoriasis and, potentially, other autoimmune diseases with an involvement of CCR6/CCL20 axis and the IL-17/IL-23 pathway. The data provide rationale for the further development of IDOR-1117-2520, which is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).
2025-04-01 | GSE289485 | GEO
Project description:Anti-IL-23 antibody therapies result in improvements to the underlying immunopathology of psoriasis. However, the dynamics of the immune profile after the administration of anti-IL-23 biologics, along with their association with treatment response, remain unclear investigation. We focused on guselkumab, an anti-IL-23p19 antibody, and performed a comprehensive analysis of immune cells, serum inflammatory molecules, and transcriptomics of CD4+ T cells, aiming to identify disease-modifying drug effects in psoriasis. A total of 24 biologic-naive patients were enrolled. Peripheral and skin lesional blood samples were collected at baseline and after treatment with guselkumab. We conducted FACS analysis of regulatory T cells (Tregs), resident memory T cells (TRMs), and dendritic cells, measured serum cytokine and chemokine levels, and examined gene expression changes using RNA-seq data for peripheral CD4+ T cells.
2025-09-01 | GSE290870 | GEO
Project description:Psoriasis is a chronic, debilitating, immune-mediated inflammatory skin disease. As IFN-gamma is involved in many cellular processes, including activation of T cells and dendritic cells (DCs), antigen processing and presentation, cell adhesion and trafficking, and cytokine and chemokine production, IFN-gamma-producing Th1 cells were proposed to be integral to the pathogenesis of psoriasis. Recently, IFN-gamma was shown to enhance IL-23 and IL-1 production by DCs and subsequently induce Th17 cells, important contributors to the inflammatory cascade in psoriasis lesions. To determine if IFN-gamma indeed induces the pathways leading to the development of psoriasis lesions, a single intradermal injection of IFN-gamma was administered to an area of clinically normal, non-lesional skin of psoriasis patients and biopsies were collected 24 hours later. Although there were no visible changes in the skin, IFN-gamma induced molecular and histological features characteristic of psoriasis lesions. IFN-gamma increased a number of differentially expressed genes in the skin, including many chemokines concomitant with an influx of T cells and inflammatory DCs. Furthermore, inflammatory DC products TNF, iNOS, IL-23, and TRAIL were present in IFN-gamma-treated skin. Thus, IFN-gamma, which is significantly elevated in non-lesional skin compared to healthy skin, appears to be a key pathogenic cytokine that can induce the inflammatory cascade in psoriasis. RNA was isolated from whole skin punch biopsies of either healthy or non-lesional psoraisis patients at baseline or 24 hours after placebo or IFN-g injection.
2011-11-30 | E-GEOD-32407 | biostudies-arrayexpress
Project description:γδ T cells produce the primary innate source of IL-17 (γδT17) and are known to play a critical role in autoimmune and inflammatory diseases such as psoriasis. We here reported that psoriatic condition (IL-1b and IL-23) reshaped metabolic signatures and effector function of γδT17 cells compared to homeostatic condition (IL-7). Acetyl-CoA carboxylase 1 (ACC1), a rate-limiting enzyme of fatty acid synthesis (FAS), directs the fate of IL-17-producing CD4 T cells (Th17) differentiation. However, little is known about the role of ACC1-mediated FAS in their innate IL-17-producer counterpart, γδT17 cells. We further investigated the role of FAS in γδT17 by comparing the effect of pharmacological ACC inhibitor Soraphen A (SorA) on DMSO vehicle under psoriatic conditions (IL-1b and IL-23) to provide insights for clinical implication.
2025-02-20 | PXD050505 | JPOST Repository
Project description:Psoriasis vulgaris and other chronic inflammatory diseases improve markedly with therapeutic blockade of IL-23 signaling in T cells, but the genetic mechanisms of response remain poorly understood. We single-cell transcriptomically profiled CD45+ immune cells isolated from lesional psoriatic skin before and after IL-23 blockade. In clinically responsive patients, a psoriatic transcriptional signature in skin-resident memory T cells was sharply attenuated. In contrast, poorly responsive patients were distinguished by enduring T17 cell activation, a mechanism distinct from alternative cytokine signaling or downstream resistance. Spatial transcriptomic analysis suggests that successful IL-23 blockade requires dampening of > 90% of IL-17-induced signaling in lymphocyte-adjacent keratinocytes, an unexpectedly high threshold. We also detected a subset of persistent, disease-specific T17 abnormalities in responsive patients, revealing an irreversible cell identity that may necessitate ongoing IL-23 inhibition. Collectively, our data establishes a patient-level paradigm for dissecting response to immunomodulatory treatments.
| EGAS00001007373 | EGA
Project description:A gene expression profiling study was conducted in which skin biopsy samples were collected for RNA extraction and hybridization to microarrays from patients with moderate-to-severe psoriasis who participated in the phase 1, guselkumab first-in-human randomized, double-blind, placebo-controlled trial. At week 12, significant reductions in psoriasis gene expression were observed in guselkumab-treated patients. Skin biopsy samples (n=59, LS: lesion, NL: non-lesion) were collected at baseline, weeks 1 and 12 following guselkumab treatment from patients with moderate-to-severe psoriasis for RNA extraction and microarray analysis.
2014-05-14 | E-GEOD-51440 | biostudies-arrayexpress
Project description:Background: IL-17 is the defining cytokine of the Th17, Tc17, and γδ T cell populations that plays a critical role in mediating inflammation and autoimmunity. Psoriasis vulgaris is an inflammatory skin disease mediated by Th1 and Th17 cytokines with relevant contributions of IFN-γ, TNF-α, and IL-17. Despite the pivotal role IL-17 plays in psoriasis, and in contrast to the other key mediators involved in the psoriasis cytokine cascade that are capable of inducing broad effects on keratinocytes, IL-17 was demonstrated to regulate the expression of a limited number of genes in monolayer keratinocytes cultured in vitro. Methodology/Principal Findings: Given the clinical efficacy of anti-IL-17 agents is associated with an impressive reduction in a large set of inflammatory genes, we sought a full-thickness skin model that more closely resemble in vivo epidermal architecture. Using a reconstructed human epidermis (RHE), IL-17 was able to upregulate 419 gene probes and downregulate 216 gene probes. As possible explanation for the increased gene induction in the RHE model is that CEBPβ, the transcription factor regulating IL-17-responsive genes, is expressed in differentiated KCs. Conclusions/Significance: The genes identified in IL-17-treated RHE are likely relevant to the IL-17 effects in psoriasis, since ixekizumab (anti-IL-17A agent) strongly suppressed the “RHE” genes in psoriasis patients treated in vivo with this IL-17 antagonist. RHE samples were treated with IFNg, IL-22 and IL-17 and compared with control
2014-02-28 | E-GEOD-52361 | biostudies-arrayexpress