Mechanisms of neural Toll-like Receptor 4-signaling
Final Report Abstract
Overall, most of the objectives of the project have been met. In particular, we have shown for the first time that toll-like receptors can be a subject of biased signalling. Although similar behaviour has been reported for other receptors, our consortium was the first to show this for TLR4. The resulting publication has receive a reasonable amount of attention in the field. To our surprise, aim 2 of the project (screening for endogenous ligands of TLR4) revealed that many proposed ligands including fibrinogen and HMGB1 are not directly acting via TLR4. In contrast, we were able to show that amyloid beta, a protein involved in Alzheimer`s disease development and progression, is directly acting via TLR4 and not as suggested in the literature via TLR2. This part of the project generated a valuable research resource in form of a cell line allowing screening for TLR4 ligands which has been requested by and provided to several research labs around the globe. Another highlight of this joint research effort was the visualization of monomeric and dimeric TLR4 directly in cells, which also made it to the cover of the respective issue of Science Signaling. This work not only is a starting point for other TLRs and the investigation of the dynamic equilibrium of monomeric and dimeric receptors, but also is a first molecular view on how TLR4 assembles into a functional, signalling-competent receptor.
Publications
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Controversial Role of Toll-like Receptor 4 in Adult Stem Cells. Stem Cell Rev. 2015 Aug;11(4):621-34
Zeuner M, Bieback K, Widera D
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Biased signalling is an essential feature of TLR4 in glioma cells. Biochim Biophys Acta. 2016 Dec;1863(12):3084-3095
Zeuner MT, Krüger CL, Volk K, Bieback K, Cottrell GS, Heilemann M, Widera D
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Paracrine effects of TLR4-polarised mesenchymal stromal cells are mediated by extracellular vesicles. J Transl Med. 2016 Feb 2;14:34
Zeuner MT, Patel K, Denecke B, Giebel B, Widera D
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Development and Characterisation of a Novel NF-κB Reporter Cell Line for Investigation of Neuroinflammation. Mediators Inflamm. 2017;2017:6209865
Zeuner MT, Vallance T, Vaiyapuri S, Cottrell GS, Widera D
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Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization. Sci Signal. 2017 Oct 31;10(503)
Krüger CL, Zeuner MT, Cottrell GS, Widera D, Heilemann M
