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