Synergistische Aktivierung von Entzündungsreaktionen durch extrazelluläre RNA und Liganden des Toll-like-Rezeptors-2
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Beschreibung
Synergistic activation of inflammatory responses by extracellular RNA and ligands of the Toll-like receptor-2
Extracellular RNA (exRNA) is an established damage-associated molecular pattern (DAMP) molecule. Its release due to cell stress or cell damage, such as ischemia or inflammation, has been repeatedly described. In this process, exRNA develops proinflammatory activities. Macrophages as central cells of the innate immunity are polarized by exRNA towards a pro-inflammatory M1-phenotype. Endosomal Toll-like receptors (TLRs) are discussed as receptors for exRNA, which require certain cofactors for their activation. However, the importance of these cofactors for the activation of these TLRs is not yet well understood.
The present work investigates which cofactors exRNA uses to influence the activation of macrophages by TLR. To this end, the effect of exRNA on the TNF--release of certain isolated TLR agonists was investigated.
The data of the present study show that the presence of exRNA significantly shifts the concentration-response curve of a TLR-2/6-ligand (Pam2CSK4) to the left and triggers a strong TNF--release already at a sub-threshold effective concentration of isolated TLR-2/6 ligands. This implies that exRNA together with a TLR-2-agonist is synergistically involved in cytokine release in murine macrophages. This effect could also be achieved with a TLR-2/1 agonist (Pam3CSK4). In contrast, exRNA in the presence of the TLR-4 agonist lipopolysaccharide (LPS) causes only a slight increase in TNF-α release. With the TLR-3 agonist poly I:C or the TLR-8 agonist R848, exRNA showed no effect on TNF- release. The synergistic effect of exRNA could be completely inhibited by a neutralizing antibody against TLR-2. Involvement of the NF-B signalling pathway and MAPK was also demonstrated. The effect of exRNA could be almost completely reversed by degradation using RNase 1.
The present work describes for the first time the synergistic activation of a TLR at the cell surface of macrophages by exRNA in the presence of PAMP or their derivatives. This new mode of synergistic inflammatory cell activation by which exRNA can trigger immunological responses with assistance of cofactors breaks with the dogma that exRNA must enter the endosome or cytoplasm of target cells to elicits an inflammatory effect. Other cellular functions of exRNA could also be triggered by other cofactors.
Autor*in
Heinz Frederik Noll
Themen in »Synergistische Aktivierung von Entzündungsreaktionen durch extrazelluläre RNA und Liganden des Toll-like-Rezeptors-2«
Extrazelluläre RNA Toll-like-Rezeptor 2 (TLR2) Makrophagenaktivierung Entzündungsreaktion Angeborene Immunität Signaltransduktion MAPK-Signalweg Zytokinfreisetzung Damage-Associated Molecular Patterns (DAMPs)