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MicroRNA-130a Contributes to Type-2 Classical DC-activation in Sjögren's Syndrome by Targeting Mitogen- and
Ana P Lopes1,2, Joel A G van Roon1,2, Sofie L M Blokland1,2
1Laboratory of Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.
Abstract:
Objectives: Considering the critical role of microRNAs (miRNAs) in regulation of cell activation, we investigated their role in circulating type-2 conventional dendritic cells (cDC2s) of patients with primary Sjögren's syndrome (pSS) compared to healthy controls (HC). Methods: CD1c-expressing cDC2s were isolated from peripheral blood. A discovery cohort (15 pSS, 6 HC) was used to screen the expression of 758 miRNAs and a replication cohort (15 pSS, 11 HC) was used to confirm differential expression of 18 identified targets. Novel targets for two replicated miRNAs were identified by SILAC in HEK-293T cells and validated in primary cDC2s. Differences in cytokine production between pSS and HC cDC2s were evaluated by intracellular flow-cytometry. cDC2s were cultured in the presence of MSK1-inhibitors to investigate their effect on cytokine production. Results: Expression of miR-130a and miR-708 was significantly decreased in cDC2s from pSS patients compared to HC in both cohorts, and both miRNAs were downregulated upon stimulation via endosomal TLRs. Upstream mediator of cytokine production MSK1 was identified as a novel target of miR-130a and overexpression of miR-130a reduced MSK1 expression in cDC2s. pSS cDC2s showed higher MSK1 expression and an increased fraction of IL-12 and TNF-α-producing cells. MSK1-inhibition reduced cDC2 activation and production of IL-12, TNF-α, and IL-6. Conclusions: The decreased expression of miR-130a and miR-708 in pSS cDC2s seems to reflect cell activation. miR-130a targets MSK1, which regulates pro-inflammatory cytokine production, and we provide proof-of-concept for MSK1-inhibition as a therapeutic avenue to impede cDC2 activity in pSS.
Insights
Decreased microRNAs (miRNAs) like miR-130a in Sjögren's syndrome patients' dendritic cells correlate with increased inflammation. Targeting MSK1, regulated by miR-130a, offers a potential therapeutic strategy for this autoimmune disease.
Area of Science:
- Immunology
- Molecular Biology
- Autoimmune Diseases
Background:
- MicroRNAs (miRNAs) are key regulators of cell activation.
- Circulating conventional type-2 dendritic cells (cDC2s) play a role in autoimmune diseases like primary Sjögren's syndrome (pSS).
Purpose of the Study:
- To investigate the role of miRNAs in cDC2s from patients with pSS compared to healthy controls (HC).
- To identify novel miRNA targets and therapeutic strategies for pSS.
Main Methods:
- miRNA expression profiling in cDC2s from pSS patients and HC.
- SILAC and flow cytometry to identify and validate miRNA targets and assess cytokine production.
- Inhibition of MSK1 to evaluate its effect on cDC2 activation and cytokine release.
Main Results:
- miR-130a and miR-708 expression were significantly decreased in pSS cDC2s.
- MSK1 was identified as a novel target of miR-130a, and its inhibition reduced pro-inflammatory cytokine production (IL-12, TNF-α, IL-6).
- pSS cDC2s exhibited higher MSK1 expression and increased IL-12 and TNF-α production.
Conclusions:
- Decreased miR-130a and miR-708 in pSS cDC2s are associated with cell activation.
- Targeting MSK1 presents a potential therapeutic avenue to modulate cDC2 activity in pSS.
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