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

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–α (TNF-α). 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-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-B 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.

Source: Signal Transduction Knowledge Environment - July 24, 2018 Category: Science Authors: Bagnall, J., Boddington, C., England, H., Brignall, R., Downton, P., Alsoufi, Z., Boyd, J., Rowe, W., Bennett, A., Walker, C., Adamson, A., Patel, N. M. X., OCualain, R., Schmidt, L., Spiller, D. G., Jackson, D. A., Müller, W., Muldoon, M., White, Tags: STKE Research Articles Source Type: news