The high expression of miR-564 in patients with systemic lupus erythematosus promotes differentiation and maturation of DC cells by negatively regulating TP53 expression in vitro

Background miRNA is involved in the occurrence and progression of systemic lupus erythematosus (SLE), but the regulatory effect of miRNA on dendritic cells in SLE patients is still unclear. Material and methods Bioinformatics methods were used to analyze the differentially expressed miRNA and its target genes in SLE patients. In vitro experiments were conducted to explore the effects and mechanisms of differentially expressed miRNAs in SLE patients on the differentiation and maturation of monocyte-derived dendritic cells. Results Bioinformatics analysis showed that miR-564 was up-regulated in SLE patients, and TP53 was the core target gene of miR-564. The expression level of miR-564 showed a rising trend during the differentiation and maturation of monocytes into Mo-DC cells. The differentiation, maturation and proliferation of Mo-DC cells were significantly inhibited by transfection with miR-564 antagomir. The expression of TP53 is negatively regulated by miR-564. In rescue experiments, the proliferation and migration of DC cells were significantly restored by co-transfection of miR-564 antagomir and TP53 si-RNA. Conclusion Highly expressed miR-564 promotes the maturation, proliferation of Mo-DC cells by negatively regulating the expression of TP53.

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Decreased miR-4512 Levels in Monocytes and Macrophages of Individuals With Systemic Lupus Erythematosus Contribute to Innate Immune Activation and Neutrsophil NETosis by Targeting TLR4 and CXCL2

Frontiers in Immunology ◽

10.3389/fimmu.2021.756825 ◽

2021 ◽

Vol 12 ◽

Author(s):

Binbin Yang ◽

Xinwei Huang ◽

Shuangyan Xu ◽

Li Li ◽

Wei Wu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Target Genes ◽

Mononuclear Cells ◽

Therapeutic Potential ◽

Luciferase Reporter ◽

Systemic Lupus ◽

Peripheral Blood Mononuclear ◽

Monocytes And Macrophages

ObjectiveSystemic lupus erythematosus (SLE) is an autoimmune disease with complex etiology that is not yet entirely understood. We aimed to elucidate the mechanisms and therapeutic potential of microRNAs (miRNAs) in SLE in a Tibetan population.MethodsPeripheral blood mononuclear cells from SLE patients (n = 5) and healthy controls (n = 5) were used for miRNA–mRNA co-sequencing to detect miRNAs related to immune abnormalities associated with SLE. Luciferase reporter assay was used to identify potential targets of candidate miRNA. The target genes were verified in miRNA-agomir/antagomir transfection assays with multiple cells lines and by expression analysis. The effects of candidate miRNA on monocyte and macrophage activation were evaluated by multiple cytokine profiling. Neutrophil extracellular traps (NETs) formation was analyzed in vitro by cell stimulation with supernatants of monocytes and macrophages transfected with candidate miRNA. The rodent MRL/lpr lupus model was used to evaluate the therapeutic effect of CXCL2Ab on SLE and the regulation effect of immune disorders.ResultsIntegrated miRNA and mRNA expression profiling identified miRNA-4512 as a candidate miRNA involved in the regulation of neutrophil activation and chemokine-related pathways. MiR-4512 expression was significantly reduced in monocytes and macrophages from SLE patients. MiR-4512 suppressed the TLR4 pathway by targeting TLR4 and CXCL2. Decreased monocyte and macrophage miR-4512 levels led to the expression of multiple proinflammatory cytokines in vitro. Supernatants of miR-4512 antagomir-transfected monocytes and macrophages significantly promoted NETs formation (P < 0.05). Blocking of CXCL2 alleviated various pathogenic manifestations in MRL/lpr mice, including kidney damage and expression of immunological markers of SLE.ConclusionsWe here demonstrated the role of miR-4512 in innate immunity regulation in SLE. The effect of miR-4512 involves the regulation of monocytes, macrophages, and NETs formation by direct targeting of TLR4 and CXCL2, indicating the miR-4512-TLR4-CXCL2 axis as a potential novel therapeutic target in SLE.

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Reconstruction and analysis of the aberrant lncRNA–miRNA–mRNA network in systemic lupus erythematosus

Lupus ◽

10.1177/0961203320908927 ◽

2020 ◽

Vol 29 (4) ◽

pp. 398-406 ◽

Cited By ~ 2

Author(s):

H Xu ◽

W Chen ◽

F Zheng ◽

D Tang ◽

D Liu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

Lupus Erythematosus ◽

Venous Blood ◽

Differentially Expressed ◽

Systemic Lupus ◽

Aberrant Expression ◽

Differentially Expressed Mirnas ◽

Non Coding Rnas ◽

New Perspective ◽

Pathway Analyses

Objective A new perspective of determining the pathophysiology of systemic lupus erythematosus (SLE) development is required. The current study explores the aberrant expression of long non-coding RNAs (lncRNA), microRNA (miRNA) and mRNA. The study further constructs and analyses the lncRNA–miRNA–mRNA network to elucidate their gene regulation roles in SLE. Method We extracted mRNA, lncRNA and miRNA from the whole venous blood of 20 SLE patients and 20 normal control (NC) healthy individuals. A lncRNA–mRNA–miRNA network in SLE was constructed using a bioinformatics approach. Subsequently, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed using the Cytoscape plug-in BinGo, the DAVID database and Cytoscape software to explore the function of mRNAs in this network. Result A total of 855 mRNA, 7311 lncRNA and 134 miRNA with differentially expressed profiles were identified. Meanwhile, we established a competing endogenous RNA (ceRNA) subnetwork composed of 52 differentially expressed lncRNAs (DElncRNAs), seven differentially expressed miRNAs and 10 differentially expressed mRNAs. We extracted the subnetwork from the ceRNA network and found that three novel miRNAs were key: hsa-miR-145, hsa-miR-17 and hsa-miR-143. We also deduced that the DElncRNAs MIAT and NEAT1 might play crucial roles in the pathogenesis of SLE. The results were verified by bioinformatics analysis. Conclusion Our results provide a novel perspective for studying lncRNA-related and miRNA-related ceRNA networks in SLE.

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SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

International Journal of Molecular Sciences ◽

10.3390/ijms22084169 ◽

2021 ◽

Vol 22 (8) ◽

pp. 4169

Author(s):

Kyoko Kawahara ◽

Tomoyuki Mukai ◽

Masanori Iseki ◽

Akiko Nagasu ◽

Hajime Nagasu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Renal Involvement ◽

Adaptor Protein ◽

Systemic Lupus ◽

Murine Systemic Lupus Erythematosus

Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells. It controls intracellular signaling pathways. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model. Methods: For the lupus model, we used Faslpr/lpr mice. Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody, and increased splenic B220+CD4−CD8− T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice. Conclusions: SH3BP2 deficiency ameliorated lupus-like manifestations. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

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Breakdown of Immune Tolerance in Systemic Lupus Erythematosus by Dendritic Cells

Journal of Immunology Research ◽

10.1155/2016/6269157 ◽

2016 ◽

Vol 2016 ◽

pp. 1-15 ◽

Cited By ~ 11

Author(s):

Xiaofeng Liao ◽

Alec M. Reihl ◽

Xin M. Luo

Keyword(s):

Systemic Lupus Erythematosus ◽

Dendritic Cells ◽

Immune Tolerance ◽

Lupus Erythematosus ◽

Treatment Strategies ◽

Systemic Lupus ◽

Lupus Pathogenesis ◽

Self Potential

Dendritic cells (DC) play an important role in the pathogenesis of systemic lupus erythematosus (SLE), an autoimmune disease with multiple tissue manifestations. In this review, we summarize recent studies on the roles of conventional DC and plasmacytoid DC in the development of both murine lupus and human SLE. In the past decade, studies using selective DC depletions have demonstrated critical roles of DC in lupus progression. Comprehensivein vitroandin vivostudies suggest activation of DC by self-antigens in lupus pathogenesis, followed by breakdown of immune tolerance to self. Potential treatment strategies targeting DC have been developed. However, many questions remain regarding the mechanisms by which DC modulate lupus pathogenesis that require further investigations.

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SH3BP2 Deficiency Ameliorates Murine Systemic Lupus Erythematosus

10.21203/rs.3.rs-74861/v1 ◽

2020 ◽

Author(s):

Kyoko Kawahara ◽

Tomoyuki Mukai ◽

Masanori Iseki ◽

Akiko Nagasu ◽

Hajime Nagasu ◽

...

Keyword(s):

Systemic Lupus Erythematosus ◽

T Cells ◽

Dendritic Cells ◽

Lupus Erythematosus ◽

Renal Involvement ◽

Systemic Lupus ◽

Dsdna Antibody ◽

Murine Systemic Lupus Erythematosus

Abstract Background: The adaptor protein Src homology 3 domain-binding protein 2 (SH3BP2) is widely expressed in immune cells, such as myeloid cells, B cells, and T cells. It controls intracellular signaling pathways, including Syk and Src. The present study was undertaken to investigate the role of SH3BP2 in a murine systemic lupus erythematosus model.Methods: For the lupus model, we used Faslpr/lpr mice (C57BL/6 background). Clinical and immunological phenotypes were compared between Faslpr/lpr and SH3BP2-deficient Faslpr/lpr mice. Splenomegaly and renal involvement were assessed in 35-week-old mice. Serum levels of anti-dsDNA antibody and rheumatoid factor were determined using ELISA. Lymphocyte subsets in the spleen were analyzed by flow cytometry. To examine the role of SH3BP2 in specific cells, B cell-specific SH3BP2-deficient lupus mice were generated and analyzed; T cells and bone marrow-derived dendritic cells and macrophages were analyzed in vitro. Results: SH3BP2 deficiency significantly reduced lupus-like phenotypes, presented as splenomegaly, renal involvement, elevated serum anti-dsDNA antibody and rheumatoid factor, and increased splenic B220+CD4-CD8- T cells. Notably, SH3BP2 deficiency in B cells did not rescue the lupus-like phenotypes. Furthermore, SH3BP2 deficiency did not substantially affect the characteristics of T cells and macrophages in vitro. Interestingly, SH3BP2 deficiency suppressed the differentiation of dendritic cells in vitro and reduced the number of dendritic cells in the spleen of the lupus-prone mice.Conclusions: SH3BP2 deficiency ameliorated clinical and immunological manifestations in lupus-prone mice, possibly via targeting dendritic cell differentiation. Modulating SH3BP2 expression could thus provide a novel therapeutic approach to autoimmune diseases.

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