Abstract
BackgroundBacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response.MethodsUsing network analysis, we defined the spatiotemporal dynamics of 20, LPS-induced, protein-level inflammatory mediators over 0–48 h in the heart, gut, lung, liver, spleen, kidney, and systemic circulation, in both C57BL/6 (wild-type) and TLR4-null mice.ResultsDynamic Network Analysis suggested that inflammation in the heart is most dependent on TLR4, followed by the liver, kidney, plasma, gut, lung, and spleen, and raises the possibility of non-TLR4 LPS signaling pathways at defined time points in the gut, lung, and spleen. Insights from computational analyses suggest an early role for TLR4-dependent tumor necrosis factor in coordinating multiple signaling pathways in the heart, giving way to later interleukin-17A—possibly derived from pathogenic Th17 cells and effector/memory T cells—in the spleen and blood.ConclusionsWe have derived novel, systems-level insights regarding the spatiotemporal evolution acute inflammation.
Highlights
Bacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response
Following binding to TLR4, LPS drives a cascade of events via MyD88 and TRIF, which regulate a multitude of inflammatory mediators in most organs
We sought to define the spatiotemporal cytokine/chemokine networks emerging from LPS/TLR4 interaction which take place simultaneously, or sequentially, within the various parenchymal organs, and that may be reflected in the systemic circulation
Summary
Bacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response. We utilized a variant of Principal Component Analysis (PCA) carried out over multiple time intervals (which we termed Time-Interval PCA [TI-PCA]) to identify organspecific inflammatory trajectories over 0–48 h following intraperitoneal administration of LPS in mice (Zamora 2018a). This analysis suggested a spatiotemporal hierarchy in which the spleen appeared to be the initial site of inflammatory activation followed by the blood (plasma), heart, liver, and gut/lung. We sought to define the spatiotemporal cytokine/chemokine networks emerging from LPS/TLR4 interaction which take place simultaneously, or sequentially, within the various parenchymal organs, and that may be reflected in the systemic circulation
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