Estrogen-regulated STAT1 activation promotes TLR8 expression to facilitate signaling via microRNA-21 in systemic lupus erythematosus

Young, Murray; Valiente, Giancarlo R.; Hampton, J.; Wu, Lai-Chu; Burd, Craig J.; Willis, William L.; Bruss, Michael; Steigelman, H; Gotsatsenko, Maya; Amici, Stephanie A.; Severin, Mary; Claverie, Lucila Marino; Guerau-de-Arellano, Mireia; Lovett-Racke, Amy E.; Ardoin, Stacy P.

doi:10.1016/j.clim.2016.12.005

Cited by 49 publications

(53 citation statements)

References 51 publications

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“…This increase in insulin export relied on enhanced EV export, as the concentration of insulin inside the EV subtypes did not change following treatment. MiRNA may act as adjuvants in immune activation and recently six miRNA with the potential to bind directly to the TLR-7 receptor of innate immunity have been described in MV and sEV 23,24,[26][27][28]48,49 . Here we wanted to investigate how TLRbinding miRNA are sorted into EV and whether their expression in these vesicles changes in situations of stress.…”

Section: Resultsmentioning

confidence: 99%

“…More recently, six specific GU-rich miRNA sequences have been identified (let-7b/c, miR-21, miR-7a, miR-29a/b) that may stimulate immune signalling by binding to the Toll-like receptor-7 (TLR-7), independently of RNAi. Packed into EV, these miRNA sequences act as DAMP exacerbating inflammation in cancer, neurological and autoimmune settings [22][23][24][25][26][27][28] .…”

Section: Introductionmentioning

confidence: 99%

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Molecular and functional diversity of distinct subpopulations of extracellular vesicles from stressed pancreatic beta cells: implications for autoimmunity

Giri

Beaurepaire

Jégou

et al. 2020

Preprint

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Beta cell failure and apoptosis following islet inflammation have been associated with autoimmune type 1 diabetes pathogenesis. As conveyors of biological active material, extracellular vesicles (EV) act as mediators in communication with immune effectors fostering the idea that EV from inflamed beta cells may contribute to autoimmunity. Evidence accumulates that beta exosomes promote diabetogenic responses, but relative contributions of larger vesicles as well as variations in the composition of the beta cell's vesiculome due to environmental changes have not been explored yet. Here, we made side-by-side comparisons of the phenotype and function of apoptotic bodies (AB), microvesicles (MV) and small EV (sEV) isolated from an equal amount of MIN6 beta cells exposed to inflammatory, hypoxic or genotoxic stressors. Under normal conditions, large vesicles represent 93% of the volume, but only 2% of the number of the vesicles. Our data reveal a consistently higher release of AB and sEV and to a lesser extent of MV, exclusively under inflammatory conditions commensurate with a 4-fold increase in the total volume of the vesiculome and enhanced export of immune-stimulatory material including the autoantigen insulin, microRNA, and cytokines. Whilst inflammation does not change the concentration of insulin inside the EV, specific Toll-like receptor-binding microRNA sequences preferentially partition into sEV. Exposure to inflammatory stress engenders drastic increases in the expression of monocyte chemoattractant protein 1 in all EV and of interleukin-27 solely in AB suggesting selective sorting towards EV subspecies. Functional in vitro assays in mouse dendritic cells and macrophages reveal further differences in the aptitude of EV to modulate expression of cytokines and maturation markers. These findings highlight the different quantitative and qualitative imprints of environmental changes in subpopulations of beta EV that may contribute to the spread of inflammation and sustained immune cell recruitment at the inception of the (auto-) immune response.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular and functional diversity of distinct subpopulations of extracellular vesicles from stressed pancreatic beta cells: implications for autoimmunity

Giri

Beaurepaire

Jégou

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…The latest research shows that EVs carry specific miRNA that activate TLR8 and subsequently stimulate the innate immune system. This research describes a new inflammatory pathway for SLE . It was also reported that there are cell‐free nucleic acids present in the mother's circulation, either in the form of apoptotic bodies or as so‐called syncytiotrophoblast debris (EVs that contain RNA or DNA), during pregnancy.…”

Section: Introductionmentioning

confidence: 94%

“…This research describes a new inflammatory pathway for SLE. 93 It was also reported that there are cell-free nucleic acids present in the mother's circulation, either in the form of apoptotic bodies or as so-called syncytiotrophoblast debris (EVs that contain RNA or DNA), during pregnancy. These cell-free nucleic acids are increased during FGR as well as PE.…”

Section: Immune Response To Evs During Various Pregnancy Complicationsmentioning

confidence: 99%

Immune activation by nucleic acids: A role in pregnancy complications

2018

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Cell-free self-DNA or RNA may induce an immune response by activating specific sensing receptors. During pregnancy, placental nucleic acids present in the maternal circulation further activate these receptors due to the presence of unmethylated CpG islands. A higher concentration of cell-free foetal DNA is associated with pregnancy complications and a higher risk for foetal rejection. Cell-free foetal DNA originates from placental trophoblasts. It appears in different forms: free, bound to histones in nucleosomes, in neutrophil extracellular traps (NETs) and in extracellular vesicles (EVs). In several pregnancy complications, cell-free foetal DNA triggers the production of proinflammatory cytokines, and this production results in a cellular and humoral immune response. This review discusses preeclampsia, systemic lupus erythematosus, foetal growth restriction, gestational diabetes, rheumatoid arthritis and obesity in pregnancy from an immunological point of view and closely examines the different pathways that result in maternal inflammation. Understanding the role of cell-free nucleic acids, as well as the biogenesis of NETs and EVs, will help us to specify their functions or targets, which seem to be important in pregnancy complications. It is still not clear whether higher concentrations of cell-free nucleic acids in the maternal circulation are the cause or consequence of various complications. Therefore, further clinical studies and, even more importantly, animal experiments that focus on the involved immunological pathways are needed.

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“…In MCF-7 cells, MIR21 is upregulated by the ESR2 selective ligand diarylpropionitrile (DPN) [104]. In systemic lupus erythematosus, estrogen-regulated STAT1 activates and promotes TLR8 expression via MIR21 [105]. Both the expression and functional loss of STAT1 are related to the development of mammary adenocarcinomas [106].…”

Section: Mir21mentioning

confidence: 99%