Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin

Jill Moser, Peter Heeringa, Rianne M Jongman, Peter J Zwiers, Anita E Niemarkt, Rui Yan, Inge A de Graaf, Ranran Li, Erzsébet Ravasz Regan, Philipp Kümpers, William C Aird, Geerten P van Nieuw Amerongen, Jan G Zijlstra, Grietje Molema, Matijs van Meurs

Research output: Contribution to journalArticleAcademicpeer-review

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.

Original languageEnglish
Pages (from-to)4681-91
Number of pages11
JournalJournal of Immunology
Volume196
Issue number11
DOIs
Publication statusPublished - 1 Jun 2016

Cite this

Moser, J., Heeringa, P., Jongman, R. M., Zwiers, P. J., Niemarkt, A. E., Yan, R., ... van Meurs, M. (2016). Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin. Journal of Immunology, 196(11), 4681-91. https://doi.org/10.4049/jimmunol.1501819
Moser, Jill ; Heeringa, Peter ; Jongman, Rianne M ; Zwiers, Peter J ; Niemarkt, Anita E ; Yan, Rui ; de Graaf, Inge A ; Li, Ranran ; Ravasz Regan, Erzsébet ; Kümpers, Philipp ; Aird, William C ; van Nieuw Amerongen, Geerten P ; Zijlstra, Jan G ; Molema, Grietje ; van Meurs, Matijs. / Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin. In: Journal of Immunology. 2016 ; Vol. 196, No. 11. pp. 4681-91.
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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.",
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author = "Jill Moser and Peter Heeringa and Jongman, {Rianne M} and Zwiers, {Peter J} and Niemarkt, {Anita E} and Rui Yan and {de Graaf}, {Inge A} and Ranran Li and {Ravasz Regan}, Erzs{\'e}bet and Philipp K{\"u}mpers and Aird, {William C} and {van Nieuw Amerongen}, {Geerten P} and Zijlstra, {Jan G} and Grietje Molema and {van Meurs}, Matijs",
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Moser, J, Heeringa, P, Jongman, RM, Zwiers, PJ, Niemarkt, AE, Yan, R, de Graaf, IA, Li, R, Ravasz Regan, E, Kümpers, P, Aird, WC, van Nieuw Amerongen, GP, Zijlstra, JG, Molema, G & van Meurs, M 2016, 'Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin' Journal of Immunology, vol. 196, no. 11, pp. 4681-91. https://doi.org/10.4049/jimmunol.1501819

Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin. / Moser, Jill; Heeringa, Peter; Jongman, Rianne M; Zwiers, Peter J; Niemarkt, Anita E; Yan, Rui; de Graaf, Inge A; Li, Ranran; Ravasz Regan, Erzsébet; Kümpers, Philipp; Aird, William C; van Nieuw Amerongen, Geerten P; Zijlstra, Jan G; Molema, Grietje; van Meurs, Matijs.

In: Journal of Immunology, Vol. 196, No. 11, 01.06.2016, p. 4681-91.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Intracellular RIG-I Signaling Regulates TLR4-Independent Endothelial Inflammatory Responses to Endotoxin

AU - Moser, Jill

AU - Heeringa, Peter

AU - Jongman, Rianne M

AU - Zwiers, Peter J

AU - Niemarkt, Anita E

AU - Yan, Rui

AU - de Graaf, Inge A

AU - Li, Ranran

AU - Ravasz Regan, Erzsébet

AU - Kümpers, Philipp

AU - Aird, William C

AU - van Nieuw Amerongen, Geerten P

AU - Zijlstra, Jan G

AU - Molema, Grietje

AU - van Meurs, Matijs

N1 - Copyright © 2016 by The American Association of Immunologists, Inc.

PY - 2016/6/1

Y1 - 2016/6/1

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.4049/jimmunol.1501819

DO - 10.4049/jimmunol.1501819

M3 - Article

VL - 196

SP - 4681

EP - 4691

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 11

ER -