Instytut Podstawowych Problemów Techniki
Polskiej Akademii Nauk

Partnerzy

Zainab Alsoufi


Ostatnie publikacje
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, 2018

Streszczenie:
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.

Afiliacje autorów:
Bagnall J. - inna afiliacja
Boddington C. - inna afiliacja
England H. - inna afiliacja
Brignall R. - inna afiliacja
Downton P. - inna afiliacja
Alsoufi Z. - inna afiliacja
Boyd J. - inna afiliacja
Rowe W. - inna afiliacja
Bennett A. - inna afiliacja
Walker C. - inna afiliacja
Adamson A. - inna afiliacja
Patel Nisha M. X. - inna afiliacja
O’Cualain R. - inna afiliacja
Schmidt L. - inna afiliacja
Spiller David G. - inna afiliacja
Jackson Dean A. - inna afiliacja
Müller W. - inna afiliacja
Muldoon M. - inna afiliacja
White Michael R. H.R. - University of Manchester (GB)
Paszek P. - inna afiliacja
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