title: Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin.
abstract: Sepsis is a systemic inflammatory response to infections associated with organ failure that is the most frequent cause of death in hospitalized patients. Exaggerated endothelial activation, altered blood flow, vascular leakage, and other disturbances synergistically contribute to sepsis-induced organ failure. The underlying signaling events associated with endothelial proinflammatory activation are not well understood, yet they likely consist of molecular pathways that act in an endothelium-specific manner. We found that LPS, a critical factor in the pathogenesis of sepsis, is internalized by endothelial cells, leading to intracellular signaling without the need for priming as found recently in immune cells. By identifying a novel role for retinoic acid-inducible gene-I (RIG-I) as a central regulator of endothelial activation functioning independent of TLR4, we provide evidence that the current paradigm of TLR4 solely being responsible for LPS-mediated endothelial responses is incomplete. RIG-I, as well as the adaptor protein mitochondrial antiviral signaling protein, regulates NF-κB-mediated induction of adhesion molecules and proinflammatory cytokine expression in response to LPS. Our findings provide essential new insights into the proinflammatory signaling pathways in endothelial cells and suggest that combined endothelial-specific inhibition of RIG-I and TLR4 will provide protection from aberrant endothelial responses associated with sepsis.
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Jill
authors.identifier: 0000-0002-9614-2577
authors.initials: J
authors.lastname: Moser
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Peter
authors.identifier: 0000-0001-8684-763X
authors.initials: P
authors.lastname: Heeringa
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Anesthesiology, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Rianne M
authors.initials: RM
authors.lastname: Jongman
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Peter J
authors.identifier: 0000-0002-6493-1897
authors.initials: PJ
authors.lastname: Zwiers
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Anita E
authors.initials: AE
authors.lastname: Niemarkt
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Rui
authors.identifier: 0000-0003-1181-3595
authors.initials: R
authors.lastname: Yan
authors.affiliation: Groningen Research Institute of Pharmacy, Division of Pharmacokinetics, Toxicology, and Targeting, University of Groningen, 9713 AV Groningen, the Netherlands;
authors.forename: Inge A
authors.initials: IA
authors.lastname: de Graaf
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Ranran
authors.initials: R
authors.lastname: Li
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215; Biochemistry and Molecular Biology Program, Department of Biology, The College of Wooster, Wooster, OH 44691;
authors.forename: Erzsébet
authors.initials: E
authors.lastname: Ravasz Regan
authors.affiliation: Division of General Internal Medicine, Nephrology, and Rheumatology, Department of Medicine D, University Hospital Muenster, 48149 Muenster, Germany; and.
authors.forename: Philipp
authors.initials: P
authors.lastname: Kümpers
authors.affiliation: Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Boston, MA 02215;
authors.forename: William C
authors.initials: WC
authors.lastname: Aird
authors.affiliation: Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands.
authors.forename: Geerten P
authors.initials: GP
authors.lastname: van Nieuw Amerongen
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Jan G
authors.identifier: 0000-0001-9079-0795
authors.initials: JG
authors.lastname: Zijlstra
authors.affiliation: Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; g.molema01@umcg.nl.
authors.forename: Grietje
authors.identifier: 0000-0002-4147-6676
authors.initials: G
authors.lastname: Molema
authors.affiliation: Department of Critical Care, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands; Department of Pathology and Medical Biology, Medical Biology Section, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, the Netherlands;
authors.forename: Matijs
authors.initials: M
authors.lastname: van Meurs
mesh_terms: D000818:Animals; D000071457:DEAD Box Protein 58 / Q000378:metabolism*; D042783:Endothelial Cells / Q000276:immunology* / Q000473:pathology; D007249:Inflammation / Q000276:immunology* / Q000473:pathology; D008070:Lipopolysaccharides / Q000276:immunology*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D015398:Signal Transduction; D051197:Toll-Like Receptor 4 / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; C503356:Ddx58 protein, mouse; D000071457:DEAD Box Protein 58