Research ArticleImmunology

Distinct single-cell signaling characteristics are conferred by the MyD88 and TRIF pathways during TLR4 activation

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Science Signaling  14 Jul 2015:
Vol. 8, Issue 385, pp. ra69
DOI: 10.1126/scisignal.aaa5208

Fine-tuning the inflammatory response

The pattern recognition receptor Toll-like receptor 4 (TLR4) binds to the bacterial product lipopolysaccharide (LPS) to induce an inflammatory response in macrophages, which depends on the transcription factor nuclear factor κB (NF-κB). At the plasma membrane, the LPS-TLR4 complex recruits the adaptor protein MyD88 (myeloid differentiation marker 88); however, upon internalization into endosomes, TLR4 recruits the adaptor protein TRIF (TIR domain–containing adaptor protein-inducing interferon-β). Through a combination of mathematical modeling and single-cell imaging analysis, Cheng et al. found that whereas MyD88 was required for the initial peak of transient NF-κB activation in all LPS-stimulated cells, TRIF was required for more sustained NF-κB activation in a subset of cells. As discussed in the Focus by Williams et al., these data suggest that macrophages use both adaptor proteins to fine-tune NF-κB activation to induce an appropriate inflammatory response.

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