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Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation

Self-extracellular RNA (eRNA), released from stressed or injured cells upon various pathological situations such as ischemia-reperfusion-injury, has been shown to act as an alarmin by inducing procoagulatory and proinflammatory responses. In particular, M1-polarization of macrophages by eRNA resulte...

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Autores principales: Noll, Frederik, Behnke, Jonas, Leiting, Silke, Troidl, Kerstin, Alves, Gustavo Teixeira, Müller-Redetzky, Holger, Preissner, Klaus T., Fischer, Silvia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738100/
https://www.ncbi.nlm.nih.gov/pubmed/29261777
http://dx.doi.org/10.1371/journal.pone.0190002
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author Noll, Frederik
Behnke, Jonas
Leiting, Silke
Troidl, Kerstin
Alves, Gustavo Teixeira
Müller-Redetzky, Holger
Preissner, Klaus T.
Fischer, Silvia
author_facet Noll, Frederik
Behnke, Jonas
Leiting, Silke
Troidl, Kerstin
Alves, Gustavo Teixeira
Müller-Redetzky, Holger
Preissner, Klaus T.
Fischer, Silvia
author_sort Noll, Frederik
collection PubMed
description Self-extracellular RNA (eRNA), released from stressed or injured cells upon various pathological situations such as ischemia-reperfusion-injury, has been shown to act as an alarmin by inducing procoagulatory and proinflammatory responses. In particular, M1-polarization of macrophages by eRNA resulted in the expression and release of a variety of cytokines, including tumor necrosis factor (TNF)-α or interleukin-6 (IL-6). The present study now investigates in which way self-eRNA may influence the response of macrophages towards various Toll-like receptor (TLR)-agonists. Isolated agonists of TLR2 (Pam2CSK4), TLR3 (PolyIC), TLR4 (LPS), or TLR7 (R848) induced the release of TNF-α in a concentration-dependent manner in murine macrophages, differentiated from bone marrow-derived stem cells by mouse colony stimulating factor. Here, the presence of eRNA shifted the dose-response curve for Pam2CSK4 (Pam) considerably to the left, indicating that eRNA synergistically enhanced the cytokine liberation from macrophages even at very low Pam-levels. The synergistic activation of TLR2 by eRNA/Pam was duplicated by other TLR2-agonists such as FSL-1 or Pam3CSK4. In contrast, for TLR4-agonists such as LPS a synergistic effect of eRNA was much weaker, and was not existent for TLR3-, or TLR7-agonists. The synergistic eRNA/Pam action was dependent on the NFκB-signaling pathway as well as on p38MAP- and MEK1/ERK-kinases and was prevented by predigestion of eRNA with RNase1 or by antibodies against TLR2. Thus, the presence of self-eRNA as alarming molecule sensitizes innate immune responses towards pathogen-associated molecular patterns (PAMPs) in a synergistic way and may thereby contribute to the differentiated outcome of inflammatory responses.
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spelling pubmed-57381002017-12-29 Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation Noll, Frederik Behnke, Jonas Leiting, Silke Troidl, Kerstin Alves, Gustavo Teixeira Müller-Redetzky, Holger Preissner, Klaus T. Fischer, Silvia PLoS One Research Article Self-extracellular RNA (eRNA), released from stressed or injured cells upon various pathological situations such as ischemia-reperfusion-injury, has been shown to act as an alarmin by inducing procoagulatory and proinflammatory responses. In particular, M1-polarization of macrophages by eRNA resulted in the expression and release of a variety of cytokines, including tumor necrosis factor (TNF)-α or interleukin-6 (IL-6). The present study now investigates in which way self-eRNA may influence the response of macrophages towards various Toll-like receptor (TLR)-agonists. Isolated agonists of TLR2 (Pam2CSK4), TLR3 (PolyIC), TLR4 (LPS), or TLR7 (R848) induced the release of TNF-α in a concentration-dependent manner in murine macrophages, differentiated from bone marrow-derived stem cells by mouse colony stimulating factor. Here, the presence of eRNA shifted the dose-response curve for Pam2CSK4 (Pam) considerably to the left, indicating that eRNA synergistically enhanced the cytokine liberation from macrophages even at very low Pam-levels. The synergistic activation of TLR2 by eRNA/Pam was duplicated by other TLR2-agonists such as FSL-1 or Pam3CSK4. In contrast, for TLR4-agonists such as LPS a synergistic effect of eRNA was much weaker, and was not existent for TLR3-, or TLR7-agonists. The synergistic eRNA/Pam action was dependent on the NFκB-signaling pathway as well as on p38MAP- and MEK1/ERK-kinases and was prevented by predigestion of eRNA with RNase1 or by antibodies against TLR2. Thus, the presence of self-eRNA as alarming molecule sensitizes innate immune responses towards pathogen-associated molecular patterns (PAMPs) in a synergistic way and may thereby contribute to the differentiated outcome of inflammatory responses. Public Library of Science 2017-12-20 /pmc/articles/PMC5738100/ /pubmed/29261777 http://dx.doi.org/10.1371/journal.pone.0190002 Text en © 2017 Noll et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Noll, Frederik
Behnke, Jonas
Leiting, Silke
Troidl, Kerstin
Alves, Gustavo Teixeira
Müller-Redetzky, Holger
Preissner, Klaus T.
Fischer, Silvia
Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
title Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
title_full Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
title_fullStr Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
title_full_unstemmed Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
title_short Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
title_sort self-extracellular rna acts in synergy with exogenous danger signals to promote inflammation
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5738100/
https://www.ncbi.nlm.nih.gov/pubmed/29261777
http://dx.doi.org/10.1371/journal.pone.0190002
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