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      Polyinosinic-Polycytidylic Acid Induces CXCL1 Expression in Cultured hCMEC/D3 Human Cerebral Microvascular Endothelial Cells

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          Abstract

          Objective: Brain microvascular endothelial cells are integral components of the blood-brain barrier and play a role in protecting the brain from invading microbes. CXC motif chemokine ligand 1 (CXCL1) induces the chemotaxis of neutrophils, and neutrophils are important in host defense in the brain. However, dysregulated neutrophil infiltration leads to brain diseases. Toll-like receptor 3 (TLR3) is a pattern recognition receptor that recognizes viral double-stranded RNA (dsRNA). The aim of this study was to investigate the effect of an TLR3 agonist on the expression of CXCL1 in brain vascular endothelial cells. Methods: hCMEC/D3 human cerebral microvascular endothelial cells were cultured and treated with polyinosinic-polycytidylic acid (poly IC), a potent synthetic dsRNA agonist for TLR3. The production of CXCL1 mRNA and protein was assessed by real-time RT-PCR and ELISA. The expression of CXCL1 was compared with that of CXCL8. The effect of pretreatment of cells with a NF-κB inhibitor (SN50), a p38 mitogen-activated protein kinase (MAPK) inhibitor (SB203580), a c-Jun N-terminal kinase (JNK) inhibitor (SP600125), an interferon (IFN) regulatory factor 3 inhibitor (MRT67307), and an anti-type I IFN-neutralizing antibody mixture was examined. Phosphorylation of p38 was examined using Western blotting. Results: Treating cultured hCMEC/D3 human cells with poly IC induced the expression of CXCL1 as well as another chemokine CXCL8. Pretreatment of cells with SN50, SB203580, and SP600125 decreased the induction of CXCL1 by poly IC. However, it was not affected by MRT67307 or by an anti-type I IFN-neutralizing antibody mixture. Pretreatment of cells with SN50 decreased the poly IC-induced phosphorylation of p38. Conclusions: Poly IC induces the expression of CXCL1 in hCMEC/D3 cells. NF-κB, p38 MAPK, and JNK are involved in this reaction. There is a cross-talk between NF-κB and p38, and NF-κB partially regulates phosphorylation of p38. CXCL1 produced by brain microvascular endothelial cells may contribute to the brain’s defense against viral infection and various neurological diseases associated with neutrophil accumulation.

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          Most cited references 25

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          Sensing of viral infection and activation of innate immunity by toll-like receptor 3.

          Toll-like receptors (TLRs) form a major group of transmembrane receptors that are involved in the detection of invading pathogens. Double-stranded RNA is a marker for viral infection that is recognized by TLR3. TLR3 triggering activates specific signaling pathways that culminate in the activation of NF-kappaB and IRF3 transcription factors, as well as apoptosis, enabling the host to mount an effective innate immune response through the induction of cytokines, chemokines, and other proinflammatory mediators. In this review, we describe the paradoxical role of TLR3 in innate immunity against different viruses and in viral pathogenesis but also the evidence for TLR3 as a "danger" receptor in nonviral diseases. We also discuss the structure and cellular localization of TLR3, as well as the complex signaling and regulatory events that contribute to TLR3-mediated immune responses.
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            Neutrophils promote mononuclear cell infiltration during viral-induced encephalitis.

            Neutrophils are the first infiltrating cell population to appear within the CNS during infection with the neurotropic JHM strain of mouse hepatitis virus (JHMV). To determine whether neutrophils play a role in limiting acute JHMV infection, mice were depleted of neutrophils. Infection of neutropenic animals resulted in increased levels of virus replication and mortality compared with control mice. Furthermore, neutropenia resulted in significantly reduced mononuclear leukocyte infiltration possibly due to reduced loss of blood brain barrier integrity during acute JHMV infection. These data suggest that infiltrating neutrophils are crucial for limiting virus replication during acute JHMV infection, contribute to the loss of blood brain barrier integrity and play a role in shaping adaptive immunity within the CNS.
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              Expression of CXCL1 in human endothelial cells induces angiogenesis through the CXCR2 receptor and the ERK1/2 and EGF pathways.

              Endothelial cell growth and proliferation are critical for angiogenesis; thus, greater insight into the regulation of pathological angiogenesis is greatly needed. Previous studies have reported on chemokine (C-X-C motif) ligand 1 (CXCL1) expression in epithelial cells and that secretion of CXCL1 from these epithelial cells induces angiogenesis. However, limited reports have demonstrated CXCL1 expression in endothelial cells. In this report, we present data that expand on the role of CXCL1 in human endothelial cells inducing angiogenesis. Specifically, CXCL1 is expressed and secreted from human endothelial cells. Interference of CXCL1 function using neutralizing antibodies resulted in a reduction in endothelial cell migration and viability/proliferation, the latter associated with a decrease in levels of cyclin D and cdk4. In vitro studies revealed that CXCL1 influenced neoangiogenesis through the regulation of epidermal growth factor and ERK1/2. In a xenograft angiogenesis model, interference of CXCL1 function resulted in inhibition of angiogenesis. A better understanding of the role of CXCL1 in the interactions between the endothelial and epithelial components will provide insight into how human tissues use CXCL1 to survive and thrive in a hostile environment.
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                Author and article information

                Journal
                NIM
                Neuroimmunomodulation
                10.1159/issn.1021-7401
                Neuroimmunomodulation
                S. Karger AG
                1021-7401
                1423-0216
                2020
                July 2020
                15 April 2020
                : 27
                : 1
                : 38-47
                Affiliations
                aDepartment of Neurosurgery, Hirosaki University School of Medicine, Hirosaki, Japan
                bDepartment of Vascular Biology, Hirosaki University School of Medicine, Hirosaki, Japan
                Author notes
                *Tadaatsu Imaizumi, Department of Vascular Biology, Hirosaki University School of Medicine, 5 Zaifucho, Hirosaki 036-8562 (Japan), timaizum@hirosaki-u.ac.jp
                Article
                506482 Neuroimmunomodulation 2020;27:38–47
                10.1159/000506482
                32294654
                © 2020 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 8, Pages: 10
                Categories
                Research Article

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