Biology subjects

Tsou, P.-S.

Publications and source records attributed to Tsou, P.-S..

5 recordsLinked to original sources

bioRxiv2025

Cross-disease comparison of dermatomyositis and lupus skin identifies inflammatory monocytes and JAK-1 signaling as drivers of vasculopathy in dermatomyositis

Dermatomyositis (DM) is a rare yet devastating autoimmune disease characterized by inflammatory and vasculopathic changes in skin and muscle. DM and systemic lupus erythematosus (lupus) skin lesions have overlapping clinical and histopathological features, yet disparate responses to available therapeutics. DM skin disease is often relapsing and recalcitrant. To investigate DM immunopathogenesis, non-lesional skin, lesional skin, and circulating immune cells from DM patients were analyzed using single-cell RNA-sequencing. Samples were analyzed in parallel with lesional and non-lesional lupus skin, healthy control skin, and peripheral blood. We demonstrate a pervasive type I interferon (IFN) signature in DM stroma that persists in culture and is distinguished from lupus by upregulation of VEGF and IL-18 signaling in DM keratinocytes. Furthermore, endothelial cells (ECs) in lesional DM exhibit decreased proliferation that was not observed in lupus. Using cell communication networks, we identified a population of DM-specific monocytes interacting with non-proliferating DM ECs. Co-culture of monocytes from DM patients with ECs resulted in increased EC apoptosis inhibited by JAK1 blockade. JAK1 inhibition also resulted in reversal of DM-stromal and inflammatory signatures. Together, our data provide a comprehensive cross-disease characterization of lesional and non-lesional skin of DM compared to lupus and implicate monocyte-mediated EC dysfunction in DM vasculopathy and support JAK inhibition for refractory skin disease.

immunology↗

bioRxiv2020

Inhibition of histone readers bromodomain extra-terminal proteins alleviates scleroderma fibrosis

Binding of the bromodomain and extra-terminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. This study sought to determine the anti-fibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan BET inhibitor JQ1, BRD2 inhibitor BIC1, or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed anti-fibrotic effects in an animal model of scleroderma and in patient-derived diffuse cutaneous (dc)SSc fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium signaling. The anti-fibrotic effect of BRD4 inhibition was at least in part mediated by downregulation of Ca2+/calmodulin-dependent protein kinase II (CaMKII-) and reduction of intracellular calcium concentrations. These results suggest that targeting calcium pathways or BRD4 might be novel therapeutic approaches for progressive tissue fibrosis.

pharmacology and toxicology↗

bioRxiv2018

Inhibition of EZH2 ameliorates lupus-like disease in MRL/lpr mice

ObjectivesWe previously revealed a role for EZH2 in inducing pro-inflammatory epigenetic changes in lupus CD4+ T cells. In this study, we sought to determine if inhibiting EZH2 ameliorates lupus-like disease in MRL/lpr mice.\n\nMethodsEZH2 expression levels in multiple cell types in lupus patients were evaluated using flow cytometry and mRNA expression data. Inhibition of EZH2 in MRL/lpr mice was achieved by DZNep intraperitoneal administration using a preventative and a therapeutic treatment model. Effects of DZNep on animal survival, anti-dsDNA antibody production, proteinuria, renal histopathology, cytokine production, and T and B cell numbers and percentages were assessed.\n\nResultsEZH2 expression levels were increased in whole blood, neutrophils, monocytes, B cells, and CD4+ T cells in lupus patients. In MRL/lpr mice, inhibiting EZH2 with DZNep treatment before or after disease onset improved survival and significantly reduced anti-dsDNA antibody production. DZNep-treated mice displayed a significant reduction in renal involvement, splenomegaly, and lymphadenopathy.\n\nLymphoproliferation and numbers of double-negative T cells were significantly reduced in DZNep treated mice. Concentrations of circulating cytokines and chemokines, including TNF, IFN-{gamma}, CCL2, RANTES/CCL5, IL-10, KC/CXCL1, IL-12, IL-12p40 and MIP-1{beta}/CCL4 were decreased in DZNep treated mice.\n\nConclusionsZH2 is upregulated in multiple cell types in lupus patients. Therapeutic inhibition of EZH2 abrogates lupus-like disease in MRL/lpr mice, suggesting that EZH2 inhibitors may be repurposed as a novel therapeutic option in lupus patients.

immunology↗

bioRxiv2018

Hypomethylation of STAT1 and HLA-DRB1 is associated with type-I interferon-dependent HLA-DRB1 expression in lupus CD8+ T cells

ObjectiveWe examined genome-wide DNA methylation changes in CD8+ T cells from lupus patients and controls, and investigated the functional relevance of some of these changes in lupus.\n\nMethodsGenome-wide DNA methylation of lupus and age, sex, and ethnicity-matched control CD8+ T cells was measured using the Infinium MethylationEPIC arrays. Measurement of relevant cell subsets was performed via flow cytometry. Gene expression was quantified by qPCR.\n\nResultsLupus CD8+ T cells had 188 hypomethylated CpG sites compared to healthy matched controls. Among the most hypomethylated were sites associated with HLA-DRB1. Genes involved in the type-I interferon response, including STAT1, were also found to be hypomethylated. IFN upregulated HLA-DRB1 expression on lupus but not control CD8+ T cells. Lupus and control CD8+ T cells significantly increased STAT1 mRNA levels after treatment with IFN. The expression of CIITA, a key interferon/STAT1 dependent MHC-class II regulator, is induced by IFN in lupus CD8+ T cells, but not healthy controls. Co-incubation of naive CD4+ T cells with IFN-treated CD8+ T cells led to CD4+ T cell activation, determined by increased expression of CD69, in lupus patients but not in healthy controls. This can be blocked by neutralizing antibodies targeting HLA-DR.\n\nConclusionsLupus CD8+ T cells are epigenetically primed to respond to type-I interferon. We describe an HLA-DRB1+ CD8+ T cell subset that can be induced by IFN in lupus patients. A possible pathogenic role for CD8+ T cells in lupus that is dependent upon a high type-I interferon environment and epigenetic priming warrants further characterization.

immunology↗

bioRxiv2017

Caffeine downregulates inflammatory pathways involved in autoimmunity

ObjectivesCaffeine is a widely consumed pharmacologically active product. In the present study, we focused on characterizing immunomodulatory effects of caffeine on peripheral blood mononuclear cells (PMBCs).\n\nMethodsThe effect of caffeine on gene expression profiles was initially evaluated using RNA sequencing data. Validation experiments were performed to confirm the results and examine dose-dependent effects of caffeine on PBMCs from healthy subjects. Gene expression levels were measured by real-time quantitative PCR, and cytokine production was determined using a multiplex cytokine assay.\n\nResultsCaffeine at high doses showed a robust downregulatory effect of immune-related genes in PBMCs. Functional annotation analysis of downregulated genes revealed significant enrichment in cytokine activity and in genes related to several autoimmune diseases including lupus and rheumatoid arthritis. Dose-dependent validation experiments showed significant downregulation at the mRNA levels of key inflammatory genes including STAT1, TNF, and PPARG. TNF and PPARG were suppressed even with the lowest caffeine dose tested, which corresponds to the serum concentration of caffeine after administration of one cup of coffee. Cytokine levels of IL-8, MIP-1{beta}, IL-6, IFN-{gamma}, GM-CSF, TNF, IL-2, IL-4, MCP-1, and IL-10 were decreased significantly with caffeine treatment.\n\nConclusionOur findings indicate potential downregulatory effects of caffeine on key inflammatory genes and cytokines, which play important role in autoimmunity. Further studies exploring therapeutic or disease-modulating potential of caffeine in autoimmune diseases and exploring the mechanisms involved are warranted.

immunology↗