Journal
MOLECULAR MEDICINE
Volume 27, Issue 1, Pages -Publisher
SPRINGER
DOI: 10.1186/s10020-021-00333-z
Keywords
Endotoxemia; Endotoxin; Lipopolysaccharide; TLR4; Cytokines; Chemokines; Dynamic Network Analysis; Principal Component Analysis
Funding
- NIH [RO1-GM-107231]
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The study used network analysis to define the spatiotemporal dynamics of 20 LPS-induced inflammatory mediators in different organs of mice, suggesting varying levels of TLR4 dependence in inflammation across different tissues. The computational analyses provided insights into the role of TLR4-dependent tumor necrosis factor in early inflammation, followed by interleukin-17A in later stages, potentially derived from specific T cell populations.
Background Bacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response. Methods Using 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. Results Dynamic 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. Conclusions We have derived novel, systems-level insights regarding the spatiotemporal evolution acute inflammation.
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