Global miRNA and mRNA expression profiles identify miRNA‐26a‐2‐3p‐dependent repression of IFN signature in systemic sclerosis human monocytes

Ciechomska, Marzena; Wojtaś, Bartosz; Swacha, Monika; Olesińska, Marzena; Beneš, Vladimı́r; Maśliński, Włodzimierz

doi:10.1002/eji.201948428

Cited by 15 publications

(9 citation statements)

References 41 publications

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“…In addition, ROC analysis revealed that enhanced expression of circulating miRNA-146b in sera and synovial fluids was a better disease activity biomarker than the CRP level. Similarly, miRNA-mRNA co-sequencing and functional analysis identified miRNA-26a as a new candidate which is predicted to negatively regulate IFN-regulated genes in systemic sclerosis (SSc) monocytes [54]. This implies that reduced expression of miRNA-26a may be involved in the pathogenic IFN signature in SSc monocytes.…”

Section: Role Of Mirnamentioning

confidence: 97%

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Roszkowski

Ciechomska

2021

Cells

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Monocytes/macrophages play a central role in chronic inflammatory disorders, including rheumatoid arthritis (RA). Activation of these cells results in the production of various mediators responsible for inflammation and RA pathogenesis. On the other hand, the depletion of macrophages using specific antibodies or chemical agents can prevent their synovial tissue infiltration and subsequently attenuates inflammation. Their plasticity is a major feature that helps the switch from a pro-inflammatory phenotype (M1) to an anti-inflammatory state (M2). Therefore, understanding the precise strategy targeting pro-inflammatory monocytes/macrophages should be a powerful way of inhibiting chronic inflammation and bone erosion. In this review, we demonstrate potential consequences of different epigenetic regulations on inflammatory cytokines production by monocytes. In addition, we present unique profiles of monocytes/macrophages contributing to identification of new biomarkers of disease activity or predicting treatment response in RA. We also outline novel approaches of tuning monocytes/macrophages by biologic drugs, small molecules or by other therapeutic modalities to reduce arthritis. Finally, the importance of cellular heterogeneity of monocytes/macrophages is highlighted by single-cell technologies, which leads to the design of cell-specific therapeutic protocols for personalized medicine in RA in the future.

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Section: Role Of Mirnamentioning

confidence: 97%

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Roszkowski

Ciechomska

2021

Cells

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“…Transfection of miR-26a-2-3p mimics to TLR-stimulated THP-1 cells proved that this miRNA is a negative regulator of IFN-stimulated genes. These findings suggest that miR-26a-2-3p downregulation might be responsible, at least in part, for the increased IFN production in SSc [91].…”

Section: Immune Dysfunction and Mirnasmentioning

confidence: 81%

Novel Concepts in Systemic Sclerosis Pathogenesis: Role for miRNAs

et al. 2021

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Systemic sclerosis (SSc) is a rare connective tissue disease with heterogeneous clinical phenotypes. It is characterized by the pathogenic triad: microangiopathy, immune dysfunction, and fibrosis. Epigenetic mechanisms modulate gene expression without interfering with the DNA sequence. Epigenetic marks may be reversible and their differential response to external stimuli could explain the protean clinical manifestations of SSc while offering the opportunity of targeted drug development. Small, non-coding RNA sequences (miRNAs) have demonstrated complex interactions between vasculature, immune activation, and extracellular matrices. Distinct miRNA profiles were identified in SSc skin specimens and blood samples containing a wide variety of dysregulated miRNAs. Their target genes are mainly involved in profibrotic pathways, but new lines of evidence also confirm their participation in impaired angiogenesis and aberrant immune responses. Research approaches focusing on earlier stages of the disease and on differential miRNA expression in various tissues could bring novel insights into SSc pathogenesis and validate the clinical utility of miRNAs as biomarkers and therapeutic targets.

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“…The comparison of transcriptomes between monocytes from healthy controls and monoctyes from patients with SSc revealed a dysregulation in the inflammatory pathways, including the pathway for IFN signaling (Figure 1A and Supplementary Figure 8A, available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.41737/abstract). Previous studies demonstrated that the type I IFN signature was up‐regulated in the peripheral blood of patients with SSc (23–25). Similarly, in our cohort, elevated serum levels of IFNα2 were observed (Supplementary Figure 8B [http://onlinelibrary.wiley.com/doi/10.1002/art.41737/abstract]).…”

Section: Resultsmentioning

confidence: 99%

Regulation of Monocyte Adhesion and Type I Interferon Signaling by CD52 in Patients With Systemic Sclerosis

Rudnik

Rolski

Jordan

et al. 2021

Arthritis & Rheumatology

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Objective Systemic sclerosis (SSc) is characterized by dysregulation of type I interferon (IFN) signaling. CD52 is known for its immunosuppressive functions in T cells. This study was undertaken to investigate the role of CD52 in monocyte adhesion and type I IFN signaling in patients with SSc. Methods Transcriptome profiles of circulating CD14+ monocytes from patients with limited cutaneous SSc (lcSSc), patients with diffuse cutaneous SSc (dcSSs), and healthy controls were analyzed by RNA sequencing. Levels of CD52, CD11b/integrin αΜ, and CD18/integrin β2 in whole blood were assessed by flow cytometry. CD52 expression was analyzed in relation to disease phenotype (early, lcSSc, dcSSc) and autoantibody profiles. The impact of overexpression, knockdown, and antibody blocking of CD52 was analyzed by gene and protein expression assays and functional assays. Results Pathway enrichment analysis indicated an increase in adhesion‐ and type I IFN–related genes in monocytes from SSc patients. These cells displayed up‐regulated expression of CD11b/CD18, reduced expression of CD52, and enhanced adhesion to intercellular adhesion molecule 1 and endothelial cells. Changes in CD52 expression were consistent with the SSc subtypes, as well as with immunosuppressive treatments, autoantibody profiles, and monocyte adhesion properties in patients with SSc. Overexpression of CD52 led to decreased levels of CD18 and monocyte adhesion, while knockdown of CD52 increased monocyte adhesion. Experiments with the humanized anti‐CD52 monoclonal antibody alemtuzumab in blood samples from healthy controls increased monocyte adhesion and CD11b/CD18 expression, and enhanced type I IFN responses. Monocytic CD52 expression was up‐regulated by interleukin‐4 (IL‐4)/IL‐13 via the STAT6 pathway, and was down‐regulated by lipopolysaccharide and IFNs α, β, and γ in a JAK1 and histone deacetylase IIa (HDAC IIa)–dependent manner. Conclusion Down‐regulation of the antiadhesion CD52 antigen in CD14+ monocytes represents a novel mechanism in the pathogenesis of SSc. Targeting of the IFN–HDAC–CD52 axis in monocytes might represent a new therapeutic option for patients with early SSc.

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Global miRNA and mRNA expression profiles identify miRNA‐26a‐2‐3p‐dependent repression of IFN signature in systemic sclerosis human monocytes

Cited by 15 publications

References 41 publications

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Tuning Monocytes and Macrophages for Personalized Therapy and Diagnostic Challenge in Rheumatoid Arthritis

Novel Concepts in Systemic Sclerosis Pathogenesis: Role for miRNAs

Regulation of Monocyte Adhesion and Type I Interferon Signaling by CD52 in Patients With Systemic Sclerosis

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