Journal article

Publication year: 2017

Journal: PLoS ONE

Volume number: 12

Issue number: 12

ISSN: 1932-6203

Open access status: Gold

DOI Link: https://doi.org/10.1371/journal.pone.0190002

Publisher: Public Library of Science

Abstract: 
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)-alpha 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-alpha 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 NF kappa B-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.

Harvard Citation style: Noll, F., Behnke, J., Leiting, S., Troidl, K., Alves, G., Mueller-Redetzky, H., et al. (2017) Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation, PLoS ONE, 12(12), Article e0190002. https://doi.org/10.1371/journal.pone.0190002

APA Citation style: Noll, F., Behnke, J., Leiting, S., Troidl, K., Alves, G., Mueller-Redetzky, H., Preissner, K., & Fischer, S. (2017). Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation. PLoS ONE. 12(12), Article e0190002. https://doi.org/10.1371/journal.pone.0190002