miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling

Ye, Eun-Ah; Liu, Li; Jiang, Youde; Jan, Jenny; Gaddipati, Subhash; Suvas, Susmit; Steinle, Jena J.

doi:10.1186/s12974-016-0771-8

Cited by 59 publications

(58 citation statements)

References 34 publications

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“…6). These findings are in agreement with prior reports [27,32]. Moreover, knockdown of A2aAR by transfection with miR-15 and A2aAR-siRNA induced the nuclear translocation of NF-κB p65, resulting in upregulation of IL-8 and IFN-γ expression.…”

Section: Discussionsupporting

confidence: 83%

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microRNA-15 Activates NF-κB Pathway via Down Regulating Expression of Adenosine A2 Receptor in Ulcerative Colitis

Zhang

2018

Cell Physiol Biochem

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Background/Aims: The role of miR-15 in ulcerative colitis (UC) is unclear. In this study, we found that miR-15 downregulated the expression of adenosine A2a receptor (A2aAR) in the colonic tissues of patients with UC and in HT-29 human colonic epithelial cells. Methods: The study population comprised patients with UC (n=23), irritable bowel syndrome (IBS, n=22), and healthy subjects (n = 20). The levels of miR-15, A2aAR, and protein in colon tissue biopsies were determined by real-time quantitative reverse transcription polymerase chain reaction, immunofluorescence staining, and Western blotting. The TargetScan prediction algorithm was used to identify the miR-15 binding site in the 3′-UTR of A2aAR. To assess the effects of miR-15 on A2aAR levels, HT-29 cells were transfected with miR-15 mimics. Results: Relative to expression in healthy subjects, A2aAR expression was decreased in UC patients and was similar in IBS patients. MiR-15 levels were higher in UC patients than in IBS patients or healthy subjects. A2aAR was the target of miR-15 in HT-29 cells, which downregulated A2aAR mRNA levels. MiR-15 mimics induced nuclear translocation of NF-κB p65 and upregulated the expression of IL-8 and IFN-γ in colonic epithelial cells; these effects were reversed by an miR-15 inhibitor. A2aAR knockdown confirmed that miR-15 activated the NF-κB cascade. Conclusion: Our data suggest that miR-15 modulates inflammatory and immune responses by suppressing the expression of A2aAR and regulating the NF-κB cascade.

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Section: Discussionsupporting

confidence: 83%

“…MiR-15 regulates TNF-α-mediated apoptosis in patients with liver failure [26]. Ye et al [27] suggested that miR-15a inhibits NF-κB, IL-1β, and TNFα signalling in retinal endothelial cells. A recent report suggested that the 3′-UTR of A2aAR harbours binding sites for miR-15 and miR-16 [21].…”

Section: Discussionmentioning

confidence: 99%

microRNA-15 Activates NF-κB Pathway via Down Regulating Expression of Adenosine A2 Receptor in Ulcerative Colitis

Zhang

2018

Cell Physiol Biochem

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“…Experiments were done using miR15a endothelial cell specific knockout mice (Ye et al, 2016) and overexpressing mice (Ye et al, 2017). Mice of both sexes at 3 months of age were used.…”

Section: Methodsmentioning

confidence: 99%

“…REC grown in high glucose were transfected with miR15a mimic (hsa-miR15a-5p) and a negative control (Ye et al, 2016). In addition, some normal glucose and high glucose control cell groups were treated with oligofectamine only.…”

Section: Methodsmentioning

confidence: 99%

“…In a population-based cohort study by Zampetaki et al (2010), decreased levels of microRNA-15a (miR15a) in bone marrow cells were associated with type 2 diabetes (Zampetaki et al, 2010). miR15a has been shown to inhibit inflammatory cytokines in the retina, leading to reduced retinal leukostasis, permeability, and angiogenesis in knockout and overexpressing transgenic miR15a mice (Wang et al, 2016; Ye et al, 2016). miR15a is implicated in the pathogenesis of acute coronary syndrome, developing from inflammatory processes and leading to plaque progression and thrombosis (Schroeder and Falk, 1996).…”

Section: Introductionmentioning

confidence: 99%

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miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature

Curtiss

Liu

Steinle

2018

Experimental Eye Research

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We have previously published that miR15a can reduce inflammatory cytokines, which could be key to diabetic retinal pathology. In this work, we wanted to investigate whether miR15a altered NLR pyrin domain 3 (NLRP3) proteins. Whole retinal lysates from both miR15a overexpressing mice and endothelial cell specific miR15a/16 knockout mice were used to investigate protein levels of forkhead box protein O1 (Foxo1), NLRP3, cleaved caspase 1 and interleukin-1 beta (IL-1β). Primary human retinal endothelial cells (REC) were cultured in normal and high glucose followed by transfection with a miR15a mimic for protein analyses. MiR15a expression was verified by quantitative PCR, and a luciferase binding assay was used to examine whether miR15a directly bound Foxo1. In mouse retinal lysates, loss of miR15a increased Foxo1, IL-1β, NLRP3, and cleaved caspase 1 levels. REC grown in high glucose transfected with the miR15a mimic had decreased levels of Foxo1 and NLRP3. miR15a directly binds to Foxo1. miR15a regulates NLRP3 actions in the retinal vasculature. Work in mice showed that loss of miR15a increased NLRP3 pathway signaling and Foxo1. miR15a mimics decreased levels of Foxo1 and NLRP3. Taken together, miR15a reduced inflammasome proteins and Foxo1 levels in the retinal vasculature.

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Retracted: MicroRNA‐335‐5p suppresses lower extremity deep venous thrombosis by targeted inhibition of PAI‐1 via the TLR4 signalingpathway

Bao

Zhang

Wang

et al. 2018

J of Cellular Biochemistry

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This study aims to investigate the effects of microRNA-335-5p (miR-335-5p) on lower-extremity deep vein thrombosis (LEDVT) by targeting PAI-1 through the TLR4 signaling pathway in rat models. siRNA, mimic, and inhibitor were used for transfection. The miR-335-5p expression was detected by in situ hybridization. CCK-8 assay and flow cytometry were adopted to detect proliferation, cell cycle, and apoptosis, respectively. Scratch test and Matrigel-based tube formation assay were used to detect the effect of miR-335-5p on cell migration ability and tube formation ability. A miR-335-5p lentivirus plasmid was constructed and injected into LEDVT rats. The length and weight of thrombus were measured, changes of thrombus recanalization were observed by CD34 immunohistochemistry, and levels of PAI-1 and inflammatory factors in femoral vein blood were detected by ELISA. LEDVT rats showed a higher AOD value of PAI-1, higher expression of PAI-1, NF-κB, Rac1, IL-1β, and TLR4 and a lower miR-335-5p expression. PAI-1 and miR-335-5p were negatively correlated. Compared to the blank and siRNA-NC groups, the miR-335-5p mimic and siRNA-PAI-1 groups showed declined expression of PAI-1, TLR4, NF-κB, Rac1, and IL-1β, increased proliferation and tube formation abilities, less cells in G0/G1 phase, and decreased apoptosis, decreased length and weight of thrombus, organized thrombus, increased new blood vessels, and decreased levels of PAI-1, IL-1, IL-6, and Tnf-a. miR-335-5p may suppress the occurrence and development of LEDVT in rats by repressing the activation of the TLR4 signaling pathway by targeted inhibition of PAI-1.

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miR-15a/16 reduces retinal leukostasis through decreased pro-inflammatory signaling

Cited by 59 publications

References 34 publications

microRNA-15 Activates NF-κB Pathway via Down Regulating Expression of Adenosine A2 Receptor in Ulcerative Colitis

microRNA-15 Activates NF-κB Pathway via Down Regulating Expression of Adenosine A2 Receptor in Ulcerative Colitis

miR15a regulates NLRP3 inflammasome proteins in the retinal vasculature

Retracted: MicroRNA‐335‐5p suppresses lower extremity deep venous thrombosis by targeted inhibition of PAI‐1 via the TLR4 signalingpathway

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