Characterization of Pathogenesis and Inflammatory Responses to Experimental Parechovirus Encephalitis

Human parechovirus type 3 (PeV-A3) infection has been recognized as an emerging etiologic factor causing severe nerve disease or sepsis in infants and young children. But the neuropathogenic mechanisms of PeV-A3 remain unknown. To understand the pathogenesis of PeV-A3 infection in the neuronal system, PeV-A3-mediated cytopathic effects were analyzed in human glioblastoma cells and neuroblastoma cells. PeV-A3 induced interferons and inflammatory cytokine expression in these neuronal cells. The pronounced cytopathic effects accompanied with activation of death signaling pathways of apoptosis, autophagy, and pyroptosis were detected. A new experimental disease model of parechovirus encephalitis was established. In the disease model, intracranial inoculation with PeV-A3 in C57BL/6 neonatal mice showed body weight loss, hindlimb paralysis, and approximately 20% mortality. PeV-A3 infection in the hippocampus and cortex regions of the neonatal mouse brain was revealed. Mechanistic assay supported the in vitro results, indicating detection of PeV-A3 replication, inflammatory cytokine expression, and death signaling transduction in mouse brain tissues. These in vitro and in vivo studies revealed that the activation of death signaling and inflammation responses is involved in PeV-A3-mediated neurological disorders. The present results might account for some of the PeV-A3-associated clinical manifestations.

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SOCS1/SOCS3 Immune Axis Modulates Synthetic Perturbations in IL6 Biological Circuit for Dynamical Cellular Response

10.1101/2020.08.31.276634 ◽

2020 ◽

Author(s):

Bhavnita Soni ◽

Shailza Singh

Keyword(s):

Signaling Pathway ◽

Cellular Response ◽

Inflammatory Cytokine ◽

Cytokine Expression ◽

Janus Kinase ◽

Cytokine Signaling ◽

Macrophage Phenotype ◽

Regulatory Circuit ◽

Stat Pathway

AbstractMacrophage phenotype plays a crucial role in the pathogenesis of Leishmanial infection. Pro-inflammatory cytokines are the key regulators that eliminate the infection induced by Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway. Suppressor of cytokine signaling (SOCS) is a well-known negative feedback regulator of JAK/STAT pathway. However, change in expression levels of SOCS in correlation with the establishment of infection is not well understood. Mathematical modeling of IL6 signaling pathway have helped identified the role of SOCS1 in establishment of infection. Furthermore, the ratio of SOCS1 and SOCS3 has been quantified both in silico as well as in vitro, indicating an immune axis which governs the macrophage phenotype during L. major infection. The ability of SOCS1 protein to inhibit the JAK/STAT1 signaling pathway and thereby decreasing pro-inflammatory cytokine expression makes it a strong candidate for therapeutic intervention. Using synthetic biology approaches, peptide based immuno-regulatory circuit have been designed to target the activity of SOCS1 which can restore pro-inflammatory cytokine expression during infection.

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Attenuation effects of heparin–superoxide dismutase conjugate on bleomycin-induced lung fibrosis in vivo and radiation-induced inflammatory cytokine expression in vitro

Biomedicine & Pharmacotherapy ◽

10.1016/j.biopha.2008.04.009 ◽

2009 ◽

Vol 63 (7) ◽

pp. 484-491 ◽

Cited By ~ 13

Author(s):

Jinfeng Liu ◽

Xuan Wang ◽

Fengshan Wang ◽

Li Teng ◽

Jichao Cao

Keyword(s):

Superoxide Dismutase ◽

Lung Fibrosis ◽

Inflammatory Cytokine ◽

Cytokine Expression ◽

Radiation Induced

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GPR110 (ADGRF1) mediates anti-inflammatory effects of N-docosahexaenoylethanolamine

Journal of Neuroinflammation ◽

10.1186/s12974-019-1621-2 ◽

2019 ◽

Vol 16 (1) ◽

Cited By ~ 8

Author(s):

Taeyeop Park ◽

Huazhen Chen ◽

Hee-Yong Kim

Keyword(s):

Inflammatory Cytokine ◽

Inflammatory Responses ◽

Cytokine Expression ◽

Regulatory Function ◽

Enzyme Linked Immunosorbent Assay ◽

Inflammatory Condition ◽

Wild Type ◽

Knock Out ◽

The Brain

Abstract Background Neuroinflammation is a widely accepted underlying condition for various pathological processes in the brain. In a recent study, synaptamide, an endogenous metabolite derived from docosahexaenoic acid (DHA, 22:6n-3), was identified as a specific ligand to orphan adhesion G-protein-coupled receptor 110 (GPR110, ADGRF1). Synaptamide has been shown to suppress lipopolysaccharide (LPS)-induced neuroinflammation in mice, but involvement of GPR110 in this process has not been established. In this study, we investigated the possible immune regulatory role of GPR110 in mediating the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. Methods For in vitro studies, we assessed the role of GPR110 in synaptamide effects on LPS-induced inflammatory responses in adult primary mouse microglia, immortalized murine microglial cells (BV2), primary neutrophil, and peritoneal macrophage by using quantitative PCR (qPCR) and enzyme-linked immunosorbent assay (ELISA) as well as neutrophil migration and ROS production assays. To evaluate in vivo effects, wild-type (WT) and GPR110 knock-out (KO) mice were injected with LPS intraperitoneally (i.p.) or TNF intravenously (i.v.) followed by synaptamide (i.p.), and expression of proinflammatory mediators was measured by qPCR, ELISA, and western blot analysis. Activated microglia in the brain and NF-kB activation in cells were examined microscopically after immunostaining for Iba-1 and RelA, respectively. Results Intraperitoneal (i.p.) administration of LPS increased TNF and IL-1β in the blood and induced pro-inflammatory cytokine expression in the brain. Subsequent i.p. injection of the GPR110 ligand synaptamide significantly reduced LPS-induced inflammatory responses in wild-type (WT) but not in GPR110 knock-out (KO) mice. In cultured microglia, synaptamide increased cAMP and inhibited LPS-induced proinflammatory cytokine expression by inhibiting the translocation of NF-κB subunit RelA into the nucleus. These effects were abolished by blocking synaptamide binding to GPR110 using an N-terminal targeting antibody. GPR110 expression was found to be high in neutrophils and macrophages where synaptamide also caused a GPR110-dependent increase in cAMP and inhibition of LPS-induced pro-inflammatory mediator expression. Intravenous injection of TNF, a pro-inflammatory cytokine that increases in the circulation after LPS treatment, elicited inflammatory responses in the brain which were dampened by the subsequent injection (i.p.) of synaptamide in a GPR110-dependent manner. Conclusion Our study demonstrates the immune-regulatory function of GPR110 in both brain and periphery, collectively contributing to the anti-neuroinflammatory effects of synaptamide under a systemic inflammatory condition. We suggest GPR110 activation as a novel therapeutic strategy to ameliorate inflammation in the brain as well as periphery.

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1-ethyl-3-(6-methylphenanthridine-8-il) urea modulates TLR3/9 activation and induces selective pro-inflammatory cytokine expression in vitro

Bioorganic & Medicinal Chemistry Letters ◽

10.1016/j.bmcl.2017.02.048 ◽

2017 ◽

Vol 27 (7) ◽

pp. 1530-1537 ◽

Cited By ~ 4

Author(s):

Natalija Knežević Teofilović ◽

Mahjoub Bihi ◽

Marijana Radić Stojković ◽

Lidija M. Tumir ◽

Katja Ester ◽

...

Keyword(s):

Inflammatory Cytokine ◽

Cytokine Expression

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Determination of Adhesion and Colonisation Intensity of Staphylococcus epidermidis and Pseudomonas aeruginosa on the Surface of Originally Synthesised Biomaterials in vitro and in vivo Studies, and Their Impact on Inflammatory Cytokine Expression in Tissues. Summary of the Doctoral Thesis

10.25143/prom-rsu_2016-10_dts ◽

2016 ◽

Author(s):

◽

Reinis Aigars

Keyword(s):

Pseudomonas Aeruginosa ◽

Staphylococcus Epidermidis ◽

Inflammatory Cytokine ◽

Cytokine Expression ◽

In Vivo Studies ◽

Doctoral Thesis

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Plasmodium falciparum malaria drives epigenetic reprogramming of human monocytes toward a regulatory phenotype

PLoS Pathogens ◽

10.1371/journal.ppat.1009430 ◽

2021 ◽

Vol 17 (4) ◽

pp. e1009430

Author(s):

Rajan Guha ◽

Anna Mathioudaki ◽

Safiatou Doumbo ◽

Didier Doumtabe ◽

Jeff Skinner ◽

...

Keyword(s):

Plasmodium Falciparum ◽

Inflammatory Cytokine ◽

Molecular Mechanisms ◽

Inflammatory Responses ◽

Plasmodium Falciparum Malaria ◽

Epigenetic Reprogramming ◽

Arginase 1 ◽

Epigenetic Marker ◽

Regulatory Phenotype

In malaria-naïve children and adults, Plasmodium falciparum-infected red blood cells (Pf-iRBCs) trigger fever and other symptoms of systemic inflammation. However, in endemic areas where individuals experience repeated Pf infections over many years, the risk of Pf-iRBC-triggered inflammatory symptoms decreases with cumulative Pf exposure. The molecular mechanisms underlying these clinical observations remain unclear. Age-stratified analyses of uninfected, asymptomatic Malian individuals before the malaria season revealed that monocytes of adults produced lower levels of inflammatory cytokines (IL-1β, IL-6 and TNF) in response to Pf-iRBC stimulation compared to monocytes of Malian children and malaria-naïve U.S. adults. Moreover, monocytes of Malian children produced lower levels of IL-1β and IL-6 following Pf-iRBC stimulation compared to 4–6-month-old infants. Accordingly, monocytes of Malian adults produced more IL-10 and expressed higher levels of the regulatory molecules CD163, CD206, Arginase-1 and TGM2. These observations were recapitulated in an in vitro system of monocyte to macrophage differentiation wherein macrophages re-exposed to Pf-iRBCs exhibited attenuated inflammatory cytokine responses and a corresponding decrease in the epigenetic marker of active gene transcription, H3K4me3, at inflammatory cytokine gene loci. Together these data indicate that Pf induces epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype that attenuates inflammatory responses during subsequent Pf exposure. Trial Registration: ClinicalTrials.gov NCT01322581.

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