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

Noll, Frederik ; Behnke, Jonas ; Leiting, Silke ; Troidl, Kerstin ; Alves, Gustavo Teixeira ; M├╝ller-Redetzky, Holger ; Preissner, Klaus T. ; Fischer, Silvia

Originalveröffentlichung: (2017) PLOS ONE 12(12):e0190002 doi: 10.1371/journal.pone.0190002
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URN: urn:nbn:de:hebis:26-opus-146144

Sammlung: Open Access - Publikationsfonds
Universität Justus-Liebig-Universit├Ąt Gie├čen
Institut: Institute of Biochemistry
Fachgebiet: Biologie, Chemie und Geowissenschaften fach├╝bergreifend
DDC-Sachgruppe: Medizin
Dokumentart: Aufsatz
Sprache: Englisch
Erstellungsjahr: 2017
Publikationsdatum: 20.05.2019
Kurzfassung auf Englisch: 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 NFKB-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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