The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice

Abstract Innate immunity is induced when pathogen-associated molecular patterns (PAMPs) bind host pattern recognition receptors (PRRs). Polyinosinic:polycytidylic acid [poly(I:C)] is a synthetic analogue of viral dsRNA that acts as a PAMP, inducing type I interferons (IFNs) in vertebrates. In the present study, the immunostimulatory effects of high molecular weight (HMW) poly(I:C) in rainbow trout cells were measured when bound to a cationic phytoglycogen nanoparticle (Nano-HMW). The physical characteristics of the nanoparticle itself, when bound to different lengths of dsRNA and when cell associated was evaluated. Optimal concentration and timing for innate immune stimulation was measured using the RTG-P1 reporter cell line. The immunostimulatory effects of HMW poly (I:C) was compared to Nano-HMW in vitro using the RTgutGC cell line cultured in a conventional monolayer or a transwell culture system. The ability of an activated intestinal epithelium to transmit an antiviral signal to macrophages was evaluated using a co-culture of RTgutGC cells and RTSll (a monocyte/macrophage cell). In all culture conditions, Nano-HMW was a more effective inducer of IFN-related antiviral immune responses compared to HMW poly (I:C) alone. This study introduces the use of cationic phytoglycogen nanoparticles as a novel delivery system for immunomodulatory molecules to enhance immune responses in aquatic vertebrates.

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Developmental 2,3,7,8‐tetrachlorodibenzo‐ p ‐dioxin exposure of either parent enhances the risk of necrotizing enterocolitis in neonatal mice

Birth Defects Research ◽

10.1002/bdr2.1742 ◽

2020 ◽

Vol 112 (16) ◽

pp. 1209-1223

Author(s):

Shilpa Mokshagundam ◽

Tianbing Ding ◽

Jelonia T. Rumph ◽

Madison Dallas ◽

Victoria R. Stephens ◽

...

Keyword(s):

Necrotizing Enterocolitis ◽

Neonatal Mice ◽

Tetrachlorodibenzo P Dioxin ◽

Dioxin Exposure

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DREAM Is Involved in the Genesis of Inflammation-Induced Prolabour Mediators in Human Myometrial and Amnion Cells

BioMed Research International ◽

10.1155/2018/8237087 ◽

2018 ◽

Vol 2018 ◽

pp. 1-12 ◽

Cited By ~ 1

Author(s):

Priyanka Goradia ◽

Ratana Lim ◽

Martha Lappas

Keyword(s):

Preterm Birth ◽

Mrna Expression ◽

Proinflammatory Cytokine ◽

Transcriptional Activity ◽

Regulatory Element ◽

Poly I:C ◽

Fetal Membranes ◽

Perinatal Morbidity ◽

Viral Dsrna ◽

Spontaneous Labour

Preterm birth is the primary cause of perinatal morbidity and mortality worldwide. Inflammation induces a cascade of events leading to preterm birth by activating nuclear factor-κB (NF-κB). In nongestational tissues, downstream regulatory element antagonist modulator (DREAM) regulates NF-κB activity. Our aims were to analyse DREAM expression in myometrium and fetal membranes obtained at term and preterm and to determine the effect of DREAM inhibition on prolabour mediators in primary myometrial and amnion cells. DREAM mRNA expression was significantly higher in fetal membranes obtained after spontaneous labour compared to nonlabour and in amnion from women with histological preterm chorioamnionitis when compared to amnion from women without chorioamnionitis. In primary myometrial and amnion cells, the effect of DREAM silencing by siRNA was a significant decrease in the expression of proinflammatory cytokine IL-6, the chemokines IL-8 and MCP-1, the adhesion molecule ICAM-1, MMP-9 mRNA expression and activity, and NF-κB transcriptional activity when stimulated with the proinflammatory cytokine IL-1β, the bacterial products fsl-1 or flagellin, or the viral dsRNA analogue poly(I:C). These data suggest that, in states of heightened inflammation, DREAM mRNA expression is increased and that, in myometrial and amnion cells, DREAM regulates proinflammatory and prolabour mediators which may be mediated via NF-κB.

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IGF1 is Developmentally Regulated in the Neonatal Intestine and Protects Neonatal Mice against Necrotizing Enterocolitis by Preserving the VEGF/VEGFR2 Signaling Pathway in an Animal Model

The FASEB Journal ◽

10.1096/fasebj.2019.33.1_supplement.496.29 ◽

2019 ◽

Vol 33 (S1) ◽

Author(s):

Xiaocai Yan ◽

Elizabeth Managlia ◽

Isabelle De Plaen

Keyword(s):

Animal Model ◽

Signaling Pathway ◽

Necrotizing Enterocolitis ◽

Developmentally Regulated ◽

Neonatal Mice ◽

Vegfr2 Signaling

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Elevated levels of circulating cell-free DNA and neutrophil proteins are associated with neonatal sepsis and necrotizing enterocolitis in immature mice, pigs and infants

Innate Immunity ◽

10.1177/1753425917719995 ◽

2017 ◽

Vol 23 (6) ◽

pp. 524-536 ◽

Cited By ~ 22

Author(s):

Duc Ninh Nguyen ◽

Allan Stensballe ◽

Jacqueline CY Lai ◽

Pingping Jiang ◽

Anders Brunse ◽

...

Keyword(s):

Preterm Infants ◽

Necrotizing Enterocolitis ◽

Immune Cell ◽

Late Onset ◽

Preterm Neonates ◽

Cell Free Dna ◽

Neonatal Mice ◽

Free Dna ◽

Associated Proteins ◽

Circulating Cell Free Dna

Preterm infants are highly susceptible to late-onset sepsis (LOS) and necrotizing enterocolitis (NEC), but disease pathogenesis and specific diagnostic markers are lacking. Circulating cell-free DNA (cfDNA) and immune cell-derived proteins are involved in multiple immune diseases in adults but have not been investigated in preterm neonates. We explored the relation of circulating neutrophil-associated proteins and cfDNA to LOS and/or NEC. Using a clinically relevant preterm pig model of spontaneous LOS and NEC development, we investigated neutrophil-associated proteins and cfDNA in plasma, together with cytokines in gut tissues. The changes in cfDNA levels were further studied in preterm pigs and neonatal mice with induced sepsis, and in preterm infants with or without LOS and/or NEC. Fifteen of 114 preterm pigs spontaneously developed both LOS and NEC, and they showed increased intestinal levels of IL-6 and IL-1β and plasma levels of cfDNA, neutrophil-associated proteins, and proteins involved in platelet-neutrophil interaction during systemic inflammation. The abundance of neutrophil-associated proteins highly correlated with cfDNA levels. Further, Staphylococcus epidermidis challenge of neonatal mice and preterm pigs increased plasma cfDNA levels and bacterial accumulation in the spleen. In infants, plasma cfDNA levels were elevated at LOS diagnosis and 1–6 d before NEC. In conclusion, elevated levels of plasma cfDNA and neutrophil proteins are associated with LOS and NEC diagnosis.

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A key role for Toll-like receptor-3 in disrupting the hemostasis balance on endothelial cells

Blood ◽

10.1182/blood-2008-02-137901 ◽

2009 ◽

Vol 113 (3) ◽

pp. 714-722 ◽

Cited By ~ 34

Author(s):

Aya Shibamiya ◽

Karin Hersemeyer ◽

Thomas Schmidt Wöll ◽

Daniel Sedding ◽

Jan-Marcus Daniel ◽

...

Keyword(s):

Endothelial Cells ◽

Tissue Factor ◽

Hemorrhagic Fever ◽

Poly I:C ◽

Toll Like Receptor ◽

Virus Infections ◽

Direct Stimulation ◽

Viral Dsrna ◽

Stimulation Of

AbstractVarious virus infections cause dysfunctional hemostasis and in some instances lead to the development of viral hemorrhagic fever syndrome. How do diverse viruses induce the expression of tissue factor on vascular cells? We hypothesize that a direct stimulation of pattern recognition receptors (PRR) by viral nucleic acids may be the key. Double-stranded RNA (dsRNA) is produced by many viruses and is recognized by various PRR, including Toll-like receptor-3 (TLR3). We have investigated whether poly I:C, a model for viral dsRNA, can influence cellular hemostasis. Poly I:C could up-regulate tissue factor and down-regulate thrombomodulin expression on endothelial cells but not on monocytes. The response to poly I:C was diminished upon small interfering RNA (siRNA)–mediated inhibition of TLR3, but not other PRR. In vivo, application of poly I:C induced similar changes in the aortic endothelium of mice as determined by enface microscopy. D-dimer, a circulating marker for enhanced coagulation and fibrinolysis, and tissue fibrin deposition was elevated. All the hemostasis-related responses to poly I:C, but not cytokine secretion, were blunted in TLR3−/− mice. Hence, the activation of TLR3 can induce the procoagulant state in the endothelium, and this could be relevant for understanding the mechanisms of viral stimulation of hemostasis.

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