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Sci Signal. 2018 Jul 24;11(540). pii: eaaf3998. doi: 10.1126/scisignal.aaf3998.

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

Author information

1
Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK.
2
School of Mathematics, University of Manchester, Manchester M13 9PL, UK.
3
Department of Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, UK.
4
Department of Chemistry, Centre for Analytical Science, Loughborough University, Loughborough LE11 3TU, UK.
5
Faculty of Biology, Medicine and Health, University of Manchester, Oxford Road, Manchester M13 9PT, UK. pawel.paszek@manchester.ac.uk.

Abstract

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.

PMID:
30042130
DOI:
10.1126/scisignal.aaf3998
[Indexed for MEDLINE]

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