1. | Bagnall J.♦, Boddington C.♦, England H.♦, Brignall R.♦, Downton P.♦, Alsoufi Z.♦, Boyd J.♦, Rowe W.♦, Bennett A.♦, Walker C.♦, Adamson A.♦, Patel Nisha M. X.♦, O’Cualain R.♦, Schmidt L.♦, Spiller David G.♦, Jackson Dean A.♦, Müller W.♦, Muldoon M.♦, White Michael R. H.R.♦, Paszek P.♦, Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation, Science Signaling, ISSN: 1945-0877, DOI: 10.1126/scisignal.aaf3998, Vol.11, No.540, pp.1-15, 2018Abstract: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. Affiliations:Bagnall J. | - | other affiliation | Boddington C. | - | other affiliation | England H. | - | other affiliation | Brignall R. | - | other affiliation | Downton P. | - | other affiliation | Alsoufi Z. | - | other affiliation | Boyd J. | - | other affiliation | Rowe W. | - | other affiliation | Bennett A. | - | other affiliation | Walker C. | - | other affiliation | Adamson A. | - | other affiliation | Patel Nisha M. X. | - | other affiliation | O’Cualain R. | - | other affiliation | Schmidt L. | - | other affiliation | Spiller David G. | - | other affiliation | Jackson Dean A. | - | other affiliation | Müller W. | - | other affiliation | Muldoon M. | - | other affiliation | White Michael R. H.R. | - | University of Manchester
(GB) | Paszek P. | - | other affiliation |
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