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Mathematical modeling and imaging analysis reveal the relative contributions of two adaptor proteins to the activation of NF-κB in macrophages. 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. Toll-like receptors (TLRs) recognize specific pathogen–associated molecular patterns and initiate innate immune responses through signaling pathways that depend on the adaptor proteins MyD88 (myeloid differentiation marker 88) or TRIF (TIR domain–containing adaptor protein–inducing interferon-β). TLR4, in particular, uses both adaptor proteins to activate the transcription factor nuclear factor κB (NF-κB); however, the specificity and redundancy of these two pathways remain to be elucidated. We developed a mathematical model to show how each pathway encodes distinct dynamical features of NF-κB activity and makes distinct contributions to the high variability observed in single-cell measurements. The assembly of a macromolecular signaling platform around MyD88 associated with receptors at the cell surface determined the timing of initial responses to generate a reliable, digital NF-κB signal. In contrast, ligand-induced receptor internalization into endosomes produced noisy, delayed, yet sustained NF-κB signals through TRIF. With iterative mathematical model development, we predicted the molecular mechanisms by which the MyD88- and TRIF-mediated pathways provide ligand concentration–dependent signaling dynamics that transmit information about the pathogen threat.

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