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Implication of miR-126 and miR-139-5p in Plasmacytoid Dendritic Cell Dysregulation in Systemic Sclerosis
Eleni Chouri1,2, Maojie Wang3, Maarten R Hillen1,2
1Center of Translational Immunology, University Medical Center Utrecht, Utrecht University, 3584 CX Utrecht, The Netherlands.
Abstract:
Compelling evidence shows the involvement of plasmacytoid dendritic cells (pDCs) in systemic sclerosis (SSc) pathogenesis. This study investigated whether microRNAs (miRNAs) are involved in the dysregulation of pDCs in SSc patients already at early stages. RNA from circulating pDCs was isolated from two independent cohorts of SSc patients with different disease phenotypes, and individuals with Raynaud's phenomenon, for microRNA profiling and RNA-sequencing analysis. Proteomic analysis was exploited to identify novel direct miRNA targets at the protein level. Twelve and fifteen miRNAs were differentially expressed in at least one group of patients compared to healthy controls in discovery cohort I and II, respectively. Of note, miR-126 and miR-139-5p were upregulated in both preclinical and definite SSc patients and correlated with the expression of type I interferon (IFN)-responsive genes. Toll-like receptor 9 (TLR9) stimulation of healthy pDCs upregulated the expression of both miRNAs, similarly to what was observed in patients. The proteomic analysis identified USP24 as a novel target of miR-139-5p. The expression level of USP24 was inversely correlated with miR-139-5p expression in SSc patients and induced by TLR9 stimulation in healthy pDCs. These findings demonstrated that the miRNA profile is altered in pDCs of SSc patients already at early stages of the disease and indicate their potential contribution to pDC activation observed in patients.
Insights
MicroRNAs (miRNAs) are altered in plasmacytoid dendritic cells (pDCs) of early-stage systemic sclerosis (SSc) patients. These changes may contribute to pDC activation in SSc pathogenesis.
Area of Science:
- Immunology
- Molecular Biology
- Genetics
Background:
- Plasmacytoid dendritic cells (pDCs) play a critical role in the pathogenesis of systemic sclerosis (SSc).
- The molecular mechanisms underlying pDC dysregulation in early SSc remain incompletely understood.
- MicroRNAs (miRNAs) are key regulators of gene expression and have been implicated in autoimmune diseases.
Purpose of the Study:
- To investigate the role of miRNAs in the dysregulation of pDCs in patients with early-stage SSc.
- To identify specific miRNAs and their targets involved in pDC activation in SSc.
- To explore the potential of miRNA profiling as an early diagnostic marker for SSc.
Main Methods:
- Isolation of circulating pDCs from two independent cohorts of SSc patients and healthy controls.
- Comprehensive miRNA profiling and RNA-sequencing analysis of pDCs.
- Proteomic analysis to identify direct miRNA targets at the protein level.
- Toll-like receptor 9 (TLR9) stimulation assays on pDCs.
Main Results:
- Significant differential expression of twelve and fifteen miRNAs in pDCs from SSc patients compared to controls in two cohorts.
- Upregulation of miR-126 and miR-139-5p in both preclinical and definite SSc patients, correlating with type I interferon-responsive genes.
- Identification of USP24 as a novel direct target of miR-139-5p, with inverse correlation in SSc patients and induction by TLR9 stimulation.
Conclusions:
- The miRNA profile of pDCs is altered in early-stage SSc patients.
- Specific miRNAs, such as miR-126 and miR-139-5p, may contribute to pDC activation in SSc.
- These findings highlight the potential involvement of miRNAs in SSc pathogenesis and suggest their utility as early biomarkers.
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