Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation
| Autor: | Michael R. H. White, Pawel Paszek, Christopher Boddington, Lorraine Schmidt, James Boyd, Zainab Alsoufi, James Bagnall, Ronan O’Cualain, David G. Spiller, Werner Müller, Dean A. Jackson, Polly Downton, Hazel England, Nisha M. X. Patel, Alex Bennett, Antony Adamson, William Rowe, Mark Muldoon, Ruth Brignall, Catherine Walker |
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| Jazyk: | angličtina |
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
medicine.medical_treatment Mice Transgenic Biochemistry Proinflammatory cytokine competitive uptake Mice 03 medical and health sciences Single-cell analysis macrophage activation cellular heterogeneity medicine Animals Humans Molecular Biology tissue-level regulation Cells Cultured Inflammation Toll-like receptor Tumor Necrosis Factor-alpha Chemistry Macrophages HEK 293 cells NF-kappa B NF-kappa B p50 Subunit Cell Biology Macrophage Activation Cell biology Toll-Like Receptor 4 HEK293 Cells RAW 264.7 Cells 030104 developmental biology Cytokine Immunology TLR4 toll-like receptor Tumor necrosis factor alpha Single-Cell Analysis Signal transduction Signal Transduction |
| Zdroj: | Bagnall, J, Boddington, C, England, H, Brignall, R, Downton, P, Alsoufi, Z, Boyd, J, Rowe, W, Bennett, A, Walker, C, Adamson, A, Patel, N, O'Cualain, R, Schmidt, L, Spiller, D, Jackson, D, Muller, W, Muldoon, M, White, M & Paszek, P 2018, ' Quantitative analysis of competitive cytokine signaling predicts tissue thresholds for the propagation of macrophage activation ', Science Signaling, vol. 11, no. 540, eaaf3998 . https://doi.org/10.1126/scisignal.aaf3998 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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