Research ArticleInflammation

Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation

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Sci. Signal.  24 Jul 2018:
Vol. 11, Issue 540, eaaf3998
DOI: 10.1126/scisignal.aaf3998

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Modeling TNF-α signaling by macrophages

The proinflammatory cytokine TNF-α is one of the earliest factors secreted by macrophages in response to bacterial infection. Diffusion of TNF-α throughout tissues disseminates the inflammatory response; however, without mechanisms to limit TNF-α signaling, damaging chronic inflammation would occur. Through single-cell monitoring of the dynamics of gene expression in macrophages and of TNF-α secretion and uptake by macrophages and fibroblasts, Bagnall et al. derived a mathematical model that suggests that TNF-α secreted by macrophages in tissues acts locally to drive immune responses but that it is taken up by surrounding nonimmune cells, such as fibroblasts, to limit its long-range effects in the tissue.


Toll-like receptor (TLR) signaling regulates macrophage activation and effector cytokine propagation in the constrained environment of a tissue. In macrophage populations, TLR4 stimulates the dose-dependent transcription of nuclear factor κB (NF-κB) target genes. However, using single-RNA counting, we found that individual cells exhibited a wide range (three orders of magnitude) of expression of the gene encoding the proinflammatory cytokine tumor necrosis factor–α (TNF-α). The TLR4-induced TNFA transcriptional response correlated with the extent of NF-κB signaling in the cells and their size. We compared the rates of TNF-α production and uptake in macrophages and mouse embryonic fibroblasts and generated a mathematical model to explore the heterogeneity in the response of macrophages to TLR4 stimulation and the propagation of the TNF-α signal in the tissue. The model predicts that the local propagation of the TLR4-dependent TNF-α response and cellular NF-κB signaling are limited to small distances of a few cell diameters between neighboring tissue-resident macrophages. In our predictive model, TNF-α propagation was constrained by competitive uptake of TNF-α from the environment, rather than by heterogeneous production of the cytokine. We propose that the highly constrained architecture of tissues enables effective localized propagation of inflammatory cues while avoiding out-of-context responses at longer distances.

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