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Natural product Shi-Bi-Man ameliorates psoriasis via inhibiting IL-23/Th17 axis and CXCL16-mediated endothelial activation

ABSTRACT: Purpose: We aimed to find a potential for psoriasis and to explore the mechanism of SBM to relieve psoriasis-like skin inflammation in mice. Methods: Supplementation with smear administration of SBM in the imiquimod-induced murine model, record the weight change and psoriasis Area and Severity Index (PASI) score during the whole process. Using hematoxylin-eosin staining to obverse to skin structure. Performing single-cell RNA sequencing to explore the mechanism of SBM in influencing psoriasis-like phenotype. Immunofluorescence were conducted for verification. Results: SBM remarkably alleviated the psoriasis-like phenotype. Single-cell RNA sequencing analysis shown the expression of Il17 and Il23 was diminished in keratinocytes and T cells, accompanied by a reduction in the proportion of Th17 cells. Meanwhile, endothelial cell activation was inhibited along with the expression of Cxcl16. Conclusion: In this work, we found that natural product SBM inhibited the IL-23/Th17 axis and CXCL16-mediated endothelial activation and had a good therapeutic effect on psoriasis in mice model. This work suggests the potential therapeutic value of SBM in psoriatic patients.

ORGANISM(S): Mus musculus

PROVIDER: GSE232568 | GEO | 2023/11/21

REPOSITORIES: GEO

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Single-cell transcriptomics reveals natural product Shi-Bi-Man promotes hair regeneration

Project description:Purpose: This study aimed to explore the mechanism of SBM to promote hair regeneration through single-cell transcriptomics Methods: Supplementation with intragastric administration or smear administration of SBM in artificially shaved C57BL/6 mice to observe its hair growth. Single-cell RNA sequencing were performed to explore the role of SBM for hair regeneration. Results: SBM significantly induced hair growth compared with control treatment.The results of single-cell sequencing revealed that after SBM treatment, the number of hair follicle stem cells (HFSCs) and dermal papilla cells (DPCs) increased significantly. Cell interactions and volcano maps show that interaction of FGF signaling pathway was significantly enhanced, in which FGF7 expression was especially upregulated in DPCs. In addition, Wnt signaling pathway also had a partially enhanced effect on the interactions between various cells in the skin. Network pharmacology study showed that the promotion of FGF and Wnt pathways by SBM was also enriched in alopecia diseases. Conclusion: We report that SBM has a potential effect on the promotion of hair growth by mainly activating FGF signaling pathway. The use of SBM may be a novel therapeutic option for hair loss.

2023-02-14 | GSE196677 | GEO

The ELK3-CXCL16 axis regulates NK cell cytotoxicity via the chemotactic activity of CXCL16 in TNBC

Project description:Background Triple-negative breast cancer (TNBC) is the most challenging subtype of breast cancer because of its aggressive behavior and the limited therapeutic strategies available. In the last decade, immunotherapy has become a promising treatment to prolong survival in advanced solid cancers including TNBC. However, the efficacy of immunotherapy in solid cancers remains limited because solid tumors contain few tumor-infiltrating lymphocytes. Methods A proteome profiler array was performed to identify secreted CXCL16 protein, the expression of which is regulated by ELK3 to control natural killer (NK) cell-mediated cytotoxicity. The correlation between ELK3 and CXCL16 was investigated by microarray and TCGA data analysis. NK cell cytotoxicity and migration assays were performed to examine the role of ELK3-CXCL16 in regulating the anticancer effect in TNBC. CXCL16-mediated NK cell recruitment and NK cell cytotoxicity were examined in an experimental metastasis mouse model and in an MDA-MB231 orthotopic mouse model. Results We show that targeting the ETS transcription factor ELK3 recruits immune cells including NK cells into tumors via the chemotactic activity of the chemokine. ELK3 depletion upregulated CXCL16 expression, thereby inducing NK cell recruitment to tumors and increasing NK cell cytotoxicity in TNBC . In silico analysis showed that ELK3 is negatively correlated with CXCL16 expression in breast cancer patient samples. Low expression of ELK3 and high expression of CXCL16 were associated with a better prognosis. Low expression of ELK3 and high expression of CXCL16 were associated with increased expression of NK cell-related genes. Conclusions The ELK3-CXCL16 axis regulates NK cell recruitment and increases NK cell cytotoxicity, suggesting that targeting the ELK3 gene could be an adjuvant strategy for increasing the efficacy of immunotherapy in TNBC.

2022-07-20 | GSE208584 | GEO

Suppression of molecular inflammatory pathways by Toll-like Receptor 7, 8, and 9 antagonists in a model of IL-23-induced skin inflammation

Project description:Psoriasis is a complex inflammatory disease resulting from the activation of T helper (Th) 1 and Th17 cells. Recent evidence suggests that abnormal activation of Toll-like receptors (TLRs) 7, 8 and 9 contributes to the initiation and maintenance of psoriasis. We have evaluated the effects of TLR antagonists on the gene expression profile in an IL-23-induced skin inflammation model in mice. Psoriasis-like skin lesions were induced in C57BL/6 mice by intradermal injection of IL-23 in the dorsum. Two TLR antagonists were compared: IMO-3100, an antagonist of TLRs 7 and 9, and IMO-8400, an antagonist of TLRs 7, 8 and 9, both of which previously have been shown to reduce epidermal hyperplasia in this model. Skin gene expression profiles of IL-23-induced inflammation were compared with or without TLR antagonist treatment. IL-23 injection resulted in alteration of 5100 gene probes (fold change ≥ 2, FDR < 0.05) including IL-17 pathways that are up-regulated in psoriasis vulgaris. Targeting TLRs 7, 8 and 9 with IMO-8400 resulted in modulation of more than 2300 mRNAs while targeting TLRs 7 and 9 with IMO-3100 resulted in modulation of more than 1900 mRNAs. Both agents strongly decreased IL-17A expression (>12-fold reduction), normalized IL-17 induced genes such as beta-defensin and CXCL1, and normalized aberrant expression of keratin 16 (indicating epidermal hyperplasia). These results suggest that IL-23-driven inflammation in mouse skin may be dependent on signaling mediated by TLRs 7, 8, and 9 and that these receptors represent novel therapeutic targets in psoriasis vulgaris and other diseases with similar pathophysiology. Expression profiles for mice with IL23-induced phenotype (psoriasisform) at baseline and after treatment with two doses of TLR7/8/9 antagonist and saline. Samples for nomal mice are also available

2014-01-21 | E-GEOD-50400 | biostudies-arrayexpress

Hsa-miR-31-5p controls a metabolic switch in psoriatic keratinocytes that identifies therapeutic intervention

Project description:Next to genetic alterations, it is being recognized that the cellular environment also acts as a major determinant in onset and progression of disease. In cases where different cell types contribute to the final disease outcome, this imposes environmental challenges as different cell types likely differ in their extracellular dependencies. A number of skin diseases, including psoriasis is characterized by a combination of keratinocyte hyperproliferation and immune cell activation. Activation of immune cells involves increased glucose consumption thereby intrinsicly limiting glucose availability for other cell types. Thus, these type of skin diseases require metabolic adaptations that enable coexistence between hyperproliferative keratinocytes and activated immune cells in a nutrient-limited environment. Hsa-microRNA-31-5p (miR-31) is highly expressed in keratinocytes within the psoriatic skin. Here we show that miR-31 expression in keratinocytes is induced by limited glucose availability and enables increased survival of keratinocytes under limiting glucose conditions, by increasing glutamine metabolism. In addition, miR-31 induced glutamine metabolism results in secretion of specific metabolites (aspartate and glutamate) but also secretion of immuno-modulatory factors. We show that this miR-31-induced secretory phenotype is sufficient to induce Th17 cell differentiation, a hallmark of psoriasis. Inhibition of glutaminase (GLS) using CB-839 impedes miR31-induced metabolic rewiring and secretion of immuno-modulatory factors. Concordantly, pharmacological targeting of GLS alleviated psoriasis pathology in a mouse model of psoriasis. Together our data illustrate an emerging concept of metabolic interaction across cell compartments that characterizes disease development, which can be employed to design effective treatment options for disease, as shown here for psoriasis.

2023-02-06 | PXD029030 | Pride

Molecular and cellular profilling of scalp psoriasis reveals differences and similarities compared to skin psoriasis

Project description:Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis on other skin areas. We sought to determine the cellular and mollecular phenotype of scalp psoriasis by performing a comparative analysis of scalp vs skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement, and 10 control subjects without psoriasis. Our results suggest that even in the scalp psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprinting were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with skin psoriasis which was mainly associated with activation of TNFâµ/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes. To define the transcriptomic profile of scalp skin, punch biopsies (6 mm diameter) were obtained from 20 Caucasian patients with untreated moderate to severe psoriasis with significative scalp involvement and 10 control subjects without psoriasis (N). Lesional (LS) samples were isolated from the infiltrated border of a plaque of psoriasis. Non lesional (NL) samples were taken from scalp areas with no visible psoriasis between the infiltrated plaques.

2015-11-25 | E-GEOD-75343 | biostudies-arrayexpress

Soluble adenylyl cyclase induces type 17 inflammation and is a potential therapeutic target in psoriasis

Project description:Cyclic AMP (cAMP) has a key role in psoriasis pathogenesis, as indicated by the therapeutic efficacy of phosphodiesterase inhibitors that prevent the degradation of cAMP. However, whether soluble adenylate cyclase (sAC) (encoded by the ADCY10 gene), which is an important source for cAMP, is involved in Th17 cell-mediated inflammation or could be an alternative therapeutic target in psoriasis is unknown. We have utilized the imiquimod model of murine psoriasiform dermatitis to address this question. Adcy10-/- mice had reduced erythema, scaling and swelling in the skin and Th17 cell numbers in the draining lymph nodes, compared with wild-type mice after induction of psoriasiform dermatitis with imiquimod. During Th17 polarization in vitro, naïve T cells from Adcy10-/- mice were unable to differentiate to Th17 cells and RNA-seq analysis revealed that sAC was also essential for Th17 cell activation. Interestingly, sAC did not impact Th17 lineage-defining transcription factors (such as RORc and cMAF) but rather was required for CREB-dependent gene expression. Finally, topical application of small molecule sAC inhibitors (sACi) reduced imiquimod-induced psoriasiform dermatitis and IL17 gene expression in the skin. Collectively, these findings demonstrate that sAC is a key factor for inducing type 17 inflammation in the skin and sACi could provide an alternative class of topical therapeutics for psoriasis.

2021-10-01 | GSE175470 | GEO

A single intradermal injection of IFN-gamma induces a psoriasis-like state in both non-lesional psoriatic and healthy skin

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

Dendritic cells maintain anti-tumor immunity by positioning CD8 resident memory T cells in the skin through the CXCL16-CXCR6 axis

Project description:Tissue-resident memory (TRM) T cells are emerging as critical components of the immune response to cancer; yet, requirements for their ongoing function and maintenance remain unclear. Antigen presenting cells (APC) promote TRM cell differentiation and re-activation but have not been implicated in sustaining TRM cell responses. Here, we identified a novel role for dendritic cells in supporting tissue resident memory to melanoma. We showed that CD8 TRM cells remain in close proximity to dendritic cells in the skin. Depletion of CD11c+ cells results in rapid disaggregation and eventual loss of melanoma-specific TRM cells. Additionally, we determined that TRM migration and/or persistence requires chemotaxis and adhesion mediated by the CXCR6/CXCL16 axis. The interaction between CXCR6-expressing TRM cells and CXCL16-expressing APCs was found to be critical for sustaining TRM cell-mediated tumor protection. These findings substantially expand our knowledge of APC functions in tissue resident memory T cell homeostasis and longevity.

2021-07-29 | GSE180647 | GEO

Molecular and cellular profilling of scalp psoriasis reveals differences and similarities compared to skin psoriasis

Project description:Scalp psoriasis shows a variable clinical spectrum and in many cases poses a great therapeutic challenge. However, it remains unknown whether the immune response of scalp psoriasis differs from understood pathomechanisms of psoriasis on other skin areas. We sought to determine the cellular and mollecular phenotype of scalp psoriasis by performing a comparative analysis of scalp vs skin using lesional and nonlesional samples from 20 Caucasian subjects with untreated moderate to severe psoriasis and significant scalp involvement, and 10 control subjects without psoriasis. Our results suggest that even in the scalp psoriasis is a disease of the inter-follicular skin. The immune mechanisms that mediate scalp psoriasis were found to be similar to those involved in skin psoriasis. However, the magnitude of dysregulation, number of differentially expressed genes, and enrichment of the psoriatic genomic fingerprinting were more prominent in skin lesions. Furthermore, the scalp transcriptome showed increased modulation of several gene-sets, particularly those induced by interferon-gamma, compared with skin psoriasis which was mainly associated with activation of TNF↵/L-17/IL-22-induced keratinocyte response genes. We also detected differences in expression of gene-sets involving negative regulation, epigenetic regulation, epidermal differentiation, and dendritic cell or Th1/Th17/Th22-related T-cell processes.

2015-11-25 | GSE75343 | GEO

Analysis of Th17 gene signature in the presence of CD28 costimulation in human CD4 naïve T cells

Project description:We determined differentially regulated gene expression profile in CD4 naïve T cells cultured in presence or absence of Th17 inducing cytokines (IL23+IL1β) and anti-CD28. We reported that CD28 costimulation induced Th17-suppressive gene signature.

2018-03-12 | GSE110097 | GEO

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