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

摘要

Author summary Gram-negative bacterial lipopolysaccharide (LPS) is both a central mediator of sepsis and a canonical inducer of acute inflammation via Toll-like receptor 4 (TLR4). Sepsis involves the systemic spillover of inflammation that normally remains localized in individual organs. The goal of this study was to gain insights into 1) early vs. later drivers of LPS-induced inflammation in various compartments, and 2) the systemic spillover from affected organs vs. local production of inflammatory mediators in the blood. This study involved a large number of data points on the dynamics of inflammatory mediators at the protein level, data-driven computational modeling of principal characteristics and cross-correlations, and validation of key hypotheses. In addition to verifying key mechanisms in LPS/TLR4-driven acute inflammation, this approach yielded key insights into the progression of inflammation across tissues, and also suggested the presence of TLR4-independent pathways (especially in the gut). This is, to our knowledge, the first study examining the dynamic evolution of some key inflammatory mediators and their interactions with each other in both the systemic circulation and within a number of targeted parenchymal organs in mice.