TY  - JOUR
A1  - Noll, Frederik
A1  - Behnke, Jonas
A1  - Leiting, Silke
A1  - Troidl, Kerstin
A1  - Teixeira Alves, Gustavo
A1  - Müller-Redetzky, Holger
A1  - Preissner, Klaus T.
A1  - Fischer, Silvia
T1  - Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation
T2  - PLoS one
N2  - 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.
KW  - Macrophages
KW  - Toll-like receptors
KW  - Cytokines
KW  - Immune receptor signaling
KW  - Inflammation
KW  - RNA isolation
KW  - Endotoxins
KW  - Pattern recognition receptors
Y1  - 2017
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/45199
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-451997
SN  - 1932-6203
N1  - 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.
VL  - 12
IS  - (12): e0190002
SP  - 1
EP  - 17
PB  - PLoS
CY  - Lawrence, Kan.
ER  -