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Mechanistic Investigation of Five Small-Molecule Inhibitors in the Treatment of Pemphigus Vulgaris via RNA-Seq Analysis

ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune disorder characterized by autoantibodies (AAbs) against Desmoglein 1 (DSG1) and Desmoglein 3 (DSG3) on keratinocytes, resulting in compromised cell-cell adhesion and epidermal blistering. To explore potential therapeutic targets, five small-molecule inhibitors, A66 (PI3Kα inhibitor), BIRB796 (p38 MAPK inhibitor), GW441756 (TrkA inhibitor), Selumetinib (MEK1 inhibitor), and Vandetanib (VEGFR2 inhibitor) were selected through a screen identifying compounds that reduce split formation in a human skin organ culture (HSOC) model. Each inhibitor exhibits distinct transcriptomic profiles that contribute to gene expression modulation, yet all share a common downregulation of chemokine signaling pathways associated with split formation. These inhibitors, capable of mitigating skin blistering in PV, present potential as therapeutic agents for this challenging autoimmune condition.

ORGANISM(S): Homo sapiens

PROVIDER: GSE285009 | GEO | 2025/02/10

REPOSITORIES: GEO

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Transcriptome Response and Protein Abundance are Correlated with Split Formation and Cell Detachment as Secondary Effects to Autoantibodies in Human Skin Organ Culture Models for Pemphgus Vulgaris

Project description:Pemphigus vulgaris (PV) is an autoimmune disease caused by autoantibodies (AAbs) targeting Desmoglein 1 (DSG1) or Desmoglein 3 (DSG3) on keratinocytes, leading to disrupted cell-cell adhesion and epidermal blistering. To investigate the early signaling events triggered by AAb binding, we examined transcriptomic and proteomic responses in a human skin organ culture (HSOC) model for PV. After injecting the single-chain variable fragment (scFv) PX43, which targets DSG1 and DSG3, or the mouse-derived DSG3 AAb AK23, we quantified transcriptome changes at 0, 5, 10, and 24 hours and proteome responses at 0 and 24 hours, using human or murine IgG as controls. Differential pathway regulation was analyzed over time using gene set variation and enrichment analysis, with pathway responses compared to in vitro and in situ responses of normal human epithelial keratinocytes (NHEKs) under conditions such as stretching, differentiation, migration, detachment, and acute wounding. Only PX43 induced split formation in the HSOC model, which was associated with significant transcriptomic and proteomic changes, while AK23 did not alter gene expression or protein levels. Enriched pathways in response to split formation included TNFα, Interferon α/γ, IL2-STAT5, and IL5-STAT3 signaling across all time points. The transcriptomic response closely resembled that of acute skin wounding and keratinocyte detachment, with an inverse correlation to cell stretching and differentiation and no correlation to keratinocyte migration. These findings indicate that AAbs targeting DSG1 and/or DSG3 alone do not drive broad transcriptomic or proteomic changes; rather, observed changes result from split formation, resembling the response to wounding and inflammation.

2025-02-10 | GSE285008 | GEO

Transcriptome Response to Autoantibodies in Human Primary Epidermis Keratinocyte Model for Pemphgus Vulgaris

Project description:Pemphigus vulgaris (PV) is an autoimmune disease caused by autoantibodies (AAbs) targeting Desmoglein 1 (DSG1) or Desmoglein 3 (DSG3) on keratinocytes, leading to disrupted cell-cell adhesion and epidermal blistering. To investigate the early signaling events triggered by AAb binding, we examined transcriptomic responses in a human primary epidermis keratinocyte (HPEK) model for PV. After incubating the single-chain variable fragment (scFv) PX43, which targets DSG1 and DSG3, and human IgG as control for 5h, 10h and 24h, differentially expressed genes (DEGs) and regulated pathways was analyzed using DESeq2 and pathway enrichment analysis. Few significantly differentially expressed DEGs (under 10) were identified of PX43 compared to hIgG at all three time points (5h, 10h and 24h) with adjusted pvalue below 0.05 and |log2FC| >1. Upregulated inflammatory related pathways including TNFα signaling were identified only at 24h. Correlation analysis of the log2 transformed transcripts per million (TPM) shows the very high positive correlation of PX43 and hIgG at all time points (spearman correlation above 0.9) These findings indicate that AAbs targeting DSG1 and DSG3 do not drive broad transcriptomic or proteomic changes at the HPEK model.

2025-02-10 | GSE288492 | GEO

mRNA-sequencing analysis of peripheral blood cells from an aggressive refractory pemphigus vulgaris patient

Project description:Pemphigus vulgaris (PV) is a kind of IgG-mediated autoimmune blistering disease (AIBD). The peripheral immune system plays a vital role in the pathophysiology of pemphigus vulgaris. This study aimed to explore the changes of peripheral immune cells of the patient before and after medication administration.

2021-12-04 | GSE190024 | GEO

Two opposite effects of desmoglein 3 on the growth of oral squamous cell carcinoma between anchorage -dependent and -independent conditions

Project description:Desmoglein 3 (Dsg3) is one of the desmosomal cadherins. Recent studies have reported that Dsg3 is abnormally expressed in oral squamous cell carcinoma (OSCC) and associated with tumor growth and poor survival. A role of Dsg3 in the progression of OSCC remains controversial, since both positive and negative effect on the cancer progression have been reported. Previously we have demonstrated that OSCC cells from the metastatic lymph nodes showed significantly higher DSG3 expression compared to those from the primary tumor of the same patients. Here we investigated the effect of Dsg3 expression on the growth of OSCC between anchorage-dependent (AD) and -independent (AID) conditions. Cell lines established from the primary tumor (P) and metastatic lymph nodes (LY) of three OSCC patients and two commercial OSCC cell lines were used for the experiments. Under AD conditions, Dsg3-low cell lines (Dsg3-low) had higher cell proliferation and migration ability than Dsg3-high cell lines (Dsg3-high) of the same patients. After transferred into AID conditions, all the cell lines except Dsg3-negative 7P showed increased Dsg3 expression by up to 50-fold, compared with AD conditions. Under AID conditions, all the patients showed higher cell proliferation ability in the Dsg3-high compared with Dsg3-low, which was marked contrast to AD conditions. Dsg3 knockdown under AD conditions increased the cell proliferation rate of all the cell lines except Dsg3-negative line. On the other hand, cell growth was not affected under AID conditions. These results suggested that Dsg3 may have two opposite effects on the growth of OSCC cells between AD and AID conditions, and that the involvement of molecules other than Dsg3 may also be important. Therefore, we investigated DEGs by Dsg3 knockdown under AD and AID conditions and their functions.

2024-12-24 | GSE275776 | GEO

Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor III

Project description:Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions, multiple allergies, and isolated patient keratinocytes exhibit increased pro-allergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the three tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1-/- skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17-skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1-/- mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of two Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth and treatment with a targeted therapy significantly improved skin lesions in patients.

2021-11-25 | GSE189096 | GEO

Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor II

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Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor I

2021-11-25 | GSE189094 | GEO

Epidermal Stratification Requires Retromer-Mediated Desmoglein-1 Recycling

Project description:Sorting transmembrane cargo is essential for tissue development and homeostasis. However, mechanisms of intracellular trafficking in stratified epidermis are poorly understood. Here we identify an interaction between the retromer endosomal trafficking component, VPS35, and the desmosomal cadherin, Desmoglein-1 (Dsg1). Dsg1 is specifically expressed in stratified epidermis and when properly localized on the plasma membrane of basal keratinocytes, promotes stratification. We show that the retromer drives Dsg1 recycling from the endo-lysosomal system to the plasma membrane to support stratification. The retromer-enhancing chaperone, R55, promotes the membrane localization of Dsg1 and a trafficking-deficient mutant associated with a severe inflammatory skin disorder, enhancing its ability to promote stratification. In the absence of Dsg1, retromer association with and expression of the glucose transporter GLUT1 increases, exposing a potential link between Dsg1 deficiency and epidermal metabolism. Our work provides the first evidence for retromer function in epidermal regeneration, identifying it as a potential therapeutic target.

2023-07-24 | PXD036646 | Pride

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Project description:Pemphigus, a rare autoimmune bullous disease mediated by anti-desmoglein autoantibodies, can be controlled with systemic medication like rituximab and high-dose systemic corticosteroids combined with immunosuppressants. However, some patients continue to experience chronically recurrent blisters in a specific area, requiring long-term maintenance systemic therapy. We demonstrate the presence of skin tertiary lymphoid structures (TLSs) with desmoglein-specific B cells in chronic blisters from pemphigus patients. In the skin TLSs, CD4+ T cells predominantly produced CXCL13. These clonally expanded CXCL13+CD4+ T cells exhibited features of activated Th1-like cells and downregulated genes associated with T-cell receptor-mediated signaling. Regulatory T cells (Tregs) are in direct contact with CXCL13+CD4+ memory T cells and increased CXCL13 production of CD4+ T cells through IL-2 consumption and TGF-β stimulation. Lastly, Intralesional corticosteroid injection improved chronic blisters and reduce skin TLSs in patients with pemphigus. This study concludes that skin TLSs are associated with the persistence of chronically recurrent blisters in pemphigus patients, and the microenvironmental network involving CXCL13+CD4+ T cells and Tregs within these structures plays an important role in CXCL13 production.

2023-09-10 | GSE242234 | GEO

Melanoma cells repress Desmoglein 1 in keratinocytes to promote tumor cell migration

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