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Quantitative single-molecule imaging of TLR4 reveals ligand-specific receptor dimerization

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Science Signaling  31 Oct 2017:
Vol. 10, Issue 503, eaan1308
DOI: 10.1126/scisignal.aan1308

Resolving TLR4 signaling

The pattern recognition receptor TLR4 recognizes lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria. Ligand binding to TLR4 stimulates two distinct signaling pathways, and different LPS types and their derivatives can bias signaling through either pathway depending on their composition, which has implications for the use of TLR4 agonists as vaccine adjuvants. Krüger et al. used quantitative single-molecule localization microscopy to examine the effects of co-receptors and different LPS chemotypes on the oligomeric state of TLR4 in live cells. In the presence of co-receptors, TLR4 was evenly divided between monomeric and dimeric forms. Agonistic LPS shifted the balance toward dimeric TLR4, which activated an inflammatory signaling pathway, whereas an antagonistic LPS chemotype favored monomeric receptor. This type of analysis should yield a more complete understanding of the factors underlying biased TLR4 signaling.