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

James Bagnall, Christopher Boddington, Hazel England, Ruth Brignall, Polly Downton, Zainab Alsoufi, James Boyd, William Rowe, Alex Bennett, Catherine Walker, Antony Adamson, Nisha Patel, Ronan O'Cualain, Lorraine Schmidt, David Spiller, Dean Jackson, Werner Muller, Mark Muldoon, Michael White, Pawel Paszek

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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 B (NF-B) 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  (TNF-). The TLR4-induced TNFA transcriptional response correlated with the extent of NF-B signaling in the cells and their size. We compared the rates of TNF- 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- signal in the tissue. The model predicts that the local propagation of the TLR4-dependent TNF- response and cellular NF-B signaling are limited to small distances of a few cell diameters between neighboring tissue-resident macrophages. In our predictive model, TNF- propagation was constrained by competitive uptake of TNF- 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.
Original languageEnglish
Article numbereaaf3998
Number of pages15
JournalScience Signaling
Issue number540
Early online date24 Jul 2018
Publication statusPublished - 24 Jul 2018


  • toll-like receptor
  • cellular heterogeneity
  • macrophage activation
  • tissue-level regulation
  • competitive uptake


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