Down-Regulation of MicroRNA-223 Promotes Degranulation via the PI3K/Akt Pathway by Targeting IGF-1R in Mast Cells

Wang, Quan; Zhao, Deyu; Xu, Hong; Zhou, Hui; Yang, Qianyuan; Liu, Feng; Zhou, Guoping

doi:10.1371/journal.pone.0123575

Cited by 28 publications

(23 citation statements)

References 19 publications

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“…Interestingly, miR-223 is known to be involved in and specific to hematopoiesis and is important for granulocyte differentiation. Downregulation of miR-223 can promote degranulation in RBL-2H3 MCs [5]. Inhibition of MC degranulation by miR-21 was observed in another study [6], while miR-146a was involved in MC survival [7].…”

Section: Resultsmentioning

confidence: 99%

Human Mast Cell Sensitization with IgE Increases miRNA-210 Expression

Just¹,

Ipsen²,

Kruhøffer³

et al. 2019

Int Arch Allergy Immunol

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Background: MicroRNAs (miRNAs) represent important post-transcriptional regulators with a dynamic expression profile during health and disease. Objectives: We explored the miRNA profile of human mast cells (MCs) during sensitization with IgE, during activation through IgE, and relat ed it to prostaglandin D₂ synthesis and histamine release. Method: We investigated the expression pattern of 762 miRNAs during the IgE-mediated sensitization and activation of MCs cultured from CD133+ stem cells that were isolated from allergic asthmatic patients and nonatopic controls. Results: IgE-mediated sensitization increased the expression of miRNA-210 eight-fold. This increase was sustained during IgE-mediated MC activation. Furthermore, we confirmed the increase of the miRNA-132/212 cluster after MC activation. Predicted target genes of miRNA-210/132/212 were enriched in several pathways known to be involved in MC activation. Histamine release was significantly higher in MCs from allergic patients when compared to controls, and a number of miRNAs correlated with histamine release and prostaglandin D₂ synthesis during MC activation. Conclusion: The miRNAs and analysis presented here can help to elucidate the role of miRNAs in mediator release during MC activation. We speculate that miRNA-210 could be important in MC sensitization that leads to allergic symptoms.

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Section: Resultsmentioning

confidence: 99%

Human Mast Cell Sensitization with IgE Increases miRNA-210 Expression

Just¹,

Ipsen²,

Kruhøffer³

et al. 2019

Int Arch Allergy Immunol

View full text Add to dashboard Cite

show abstract

“…Furthermore, microRNAs are being investigated as potential mechanisms to regulate MC activation. For example, microRNA‐223 targets insulin‐like growth factor 1 receptor in MCs, promoting degranulation and decreasing the phosphoinositide 3‐kinase/protein kinase B pathway …”

Section: Discussionmentioning

confidence: 99%

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

et al. 2017

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Activated mast cells (MCs) release histamine (HA) and MCs infiltrate the liver following bile duct ligation (BDL) increasing intrahepatic bile duct mass (IBDM) and fibrosis. We evaluated the effects of BDL in MC deficient mice. Methods: WT and KitW-sh mice were subjected to sham or BDL for up to 7 days and KitW-sh mice were injected with cultured mast cells or 1X PBS before collecting serum, liver blocks and cholangiocytes. Liver damage was assessed by H&E and ALT levels. IBDM was detected by CK-19 expression and proliferation by Ki-67 immunohistochemistry. Fibrosis was detected by immunohistochemistry, hydroxyproline content and by qPCR for fibrotic markers. Hepatic stellate cell (HSC) activation and TGF-β1 expression/secretion were evaluated. HDC and histamine receptor (HR) expression were detected by qPCR and HA secretion by EIA. To evaluate vascular cells, Von Willebrand (vWF) and VEGF-C expression were measured. In vitro, cultured HSCs were stimulated with cholangiocyte supernatants and α-SMA measured. Results: BDL-induced liver damage was reduced in the BDL KitW-sh mice, whereas injection of MCs did not mimic BDL-induced damage. In BDL KitW-sh mice, IBDM, proliferation, HSC activation/fibrosis and TGF-β1 expression/secretion were decreased. The HDC/HA/HR axis was ablated in sham and BDL KitW-sh mice. vWF and VEGF-C expression decreased in BDL KitW-sh mice. In KitW-sh mice injected with MCs, IBDM, proliferation, fibrosis and vascular cell activation increased. Stimulation with cholangiocyte supernatants from BDL WT or KitW-sh mice injected with MCs increased HSC activation, which decreased with supernatants from BDL KitW-sh mice. Conclusion: MCs promote hyperplasia, fibrosis and vascular cell activation. Knockout of MCs decreases BDL-induced damage. Modulation of MCs may be important in developing therapeutics for cholangiopathies.

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“…We found that expression of this miRNA was reproducibly reduced in Dnmt3a KO mast cells compared with their WT counterparts, and such reduction could also indirectly contribute to the increased ability of Dnmt3a KO mast cells to degranulate in response to acute stimulation. Indeed, down-regulation of miR-223 was recently shown to promote mast cell degranulation in response to IgE stimulation (54).…”

Section: Dysregulated Dna Methylation Activity Leads To Increased Masmentioning

confidence: 99%

Dnmt3a restrains mast cell inflammatory responses

Leoni

Montagner

Rinaldi

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

119

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DNA methylation and specifically the DNA methyltransferase enzyme DNMT3A are involved in the pathogenesis of a variety of hematological diseases and in regulating the function of immune cells. Although altered DNA methylation patterns and mutations in DNMT3A correlate with mast cell proliferative disorders in humans, the role of DNA methylation in mast cell biology is not understood. By using mast cells lacking Dnmt3a, we found that this enzyme is involved in restraining mast cell responses to acute and chronic stimuli, both in vitro and in vivo. The exacerbated mast cell responses observed in the absence of Dnmt3a were recapitulated or enhanced by treatment with the demethylating agent 5-aza-2′-deoxycytidine as well as by down-modulation of Dnmt1 expression, further supporting the role of DNA methylation in regulating mast cell activation. Mechanistically, these effects were in part mediated by the dysregulated expression of the scaffold protein IQGAP2, which is characterized by the ability to regulate a wide variety of biological processes. Altogether, our data demonstrate that DNMT3A and DNA methylation are key modulators of mast cell responsiveness to acute and chronic stimulation.DNA methylation | epigenetics | inflammation | mast cells

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Down-Regulation of MicroRNA-223 Promotes Degranulation via the PI3K/Akt Pathway by Targeting IGF-1R in Mast Cells

Cited by 28 publications

References 19 publications

Human Mast Cell Sensitization with IgE Increases miRNA-210 Expression

Human Mast Cell Sensitization with IgE Increases miRNA-210 Expression

Bile duct ligation–induced biliary hyperplasia, hepatic injury, and fibrosis are reduced in mast cell–deficient KitW‐sh mice

Dnmt3a restrains mast cell inflammatory responses

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