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

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

doi:10.1371/journal.pcbi.1006582

Abstract

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.

Highlights

Bacterial sepsis is a complex process in which a rapidly-evolving systemic and uncontrolled immune activation is initiated and perpetuated by microbial invasion [1]
Endotoxin-induced inflammation in mice 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 crosscorrelations, and validation of key hypotheses
In addition to verifying key mechanisms in LPS/Toll-like receptor 4 (TLR4)-driven acute inflammation, this approach yielded key insights into the progression of inflammation across tissues, and suggested the presence of TLR4-independent pathways. 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

Summary

Introduction

Bacterial sepsis is a complex process in which a rapidly-evolving systemic and uncontrolled immune activation is initiated and perpetuated by microbial invasion [1]. This inflammatory response can lead to a shock state and severe organ dysfunction, at times culminating in death. The lipopolysaccharide (LPS) on the outer membrane of Gram negative bacteria, has been long recognized as a potent microbial mediator in the pathogenesis of systemic inflammation in gram negative sepsis and septic shock [5, 6]. The acute administration of LPS into rodents does not fully mimic the more gradual evolving inflammatory dynamics of a replicating and disseminating bacterial infection in humans, it does serve as a means of inducing a quantifiable systemic acute inflammation that shares many of the hallmarks of bacterial sepsis [7]

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