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

Noll, FrederikFrederikNollBehnke, JonasJonasBehnkeLeiting, SilkeSilkeLeitingTroidl, KerstinKerstinTroidlAlves, Gustavo TeixeiraGustavo TeixeiraAlvesMüller-Redetzky, HolgerHolgerMüller-RedetzkyPreissner, Klaus T.Klaus T.PreissnerFischer, SilviaSilviaFischer2022-11-182019-05-202022-11-182017http://nbn-resolving.de/urn:nbn:de:hebis:26-opus-146144https://jlupub.ub.uni-giessen.de/handle/jlupub/9449http://dx.doi.org/10.22029/jlupub-8837Self-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)-Î± 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-Î± 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.enNamensnennung 4.0 Internationalddc:610Self-extracellular RNA acts in synergy with exogenous danger signals to promote inflammation