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 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.
Verfasserangaben: | Frederik Noll, Jonas Behnke, Silke Leiting, Kerstin TroidlORCiDGND, Gustavo Teixeira Alves, Holger Müller-Redetzky, Klaus T. PreissnerGND, Silvia FischerORCiDGND |
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URN: | urn:nbn:de:hebis:30:3-451997 |
DOI: | https://doi.org/10.1371/journal.pone.0190002 |
ISSN: | 1932-6203 |
Pubmed-Id: | https://pubmed.ncbi.nlm.nih.gov/29261777 |
Titel des übergeordneten Werkes (Englisch): | PLoS one |
Verlag: | PLoS |
Verlagsort: | Lawrence, Kan. |
Sonstige beteiligte Person(en): | David M. Ojcius |
Dokumentart: | Wissenschaftlicher Artikel |
Sprache: | Englisch |
Jahr der Fertigstellung: | 2017 |
Datum der Erstveröffentlichung: | 20.12.2017 |
Veröffentlichende Institution: | Universitätsbibliothek Johann Christian Senckenberg |
Datum der Freischaltung: | 21.12.2017 |
Freies Schlagwort / Tag: | Cytokines; Endotoxins; Immune receptor signaling; Inflammation; Macrophages; Pattern recognition receptors; RNA isolation; Toll-like receptors |
Jahrgang: | 12 |
Ausgabe / Heft: | (12): e0190002 |
Seitenzahl: | 17 |
Erste Seite: | 1 |
Letzte Seite: | 17 |
Bemerkung: | Copyright: © 2017 Noll et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. |
HeBIS-PPN: | 426119622 |
Institute: | Medizin / Medizin |
DDC-Klassifikation: | 6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit |
Sammlungen: | Universitätspublikationen |
Lizenz (Deutsch): | ![]() |