A Computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice

Zamora, Ruben; Korff, Sebastian; Mi, Qi; Barclay, Derek A.; Schimunek, Lukas; Zucca, Riccardo; Arsiwalla, Xerxes D.; Simmons, Richard L.; Verschure, Paul F. M. J.; Billiar, Timothy R.; Vodovotz, Yoram

doi:http://dx.doi.org/10.1371/journal.pcbi.1006582

A Computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice

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Citació

Zamora R, Korff S, Mi Q, Barclay D, Schimunek L, Zucca R, Arsiwalla XD, Simmons RL, Verschure P, Billiar TR, Vodovotz Y. A Computational analysis of dynamic, multi-organ inflammatory crosstalk induced by endotoxin in mice. PLoS Comput Biol. 2018 Nov 6;14(11):e1006582. DOI: 10.1371/journal.pcbi.1006582

Resum

Bacterial lipopolysaccharide (LPS) induces an acute inflammatory response across multiple organs, primarily via Toll-like receptor 4 (TLR4). We sought to define novel aspects of the complex spatiotemporal dynamics of LPS-induced inflammation using computational modeling, with a special focus on the timing of pathological systemic spillover. An analysis of principal drivers of LPS-induced inflammation in the heart, gut, lung, liver, spleen, and kidney to assess organ-specific dynamics, as well as in the plasma (as an assessment of systemic spillover), was carried out using data on 20 protein-level inflammatory mediators measured over 0-48h in both C57BL/6 and TLR4-null mice. Using a suite of computational techniques, including a time-interval variant of Principal Component Analysis, we confirm key roles for cytokines such as tumor necrosis factor-α and interleukin-17A, define a temporal hierarchy of organ-localized inflammation, and infer the point at which organ-localized inflammation spills over systemically. Thus, by employing a systems biology approach, we obtain a novel perspective on the time- and organ-specific components in the propagation of acute systemic inflammation.