Spatiotemporally specific roles of TLR4, TNF, and IL-17A in murine endotoxin-induced inflammation inferred from analysis of dynamic networks

Abstract

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.

Inferring Tissue-Specific, TLR4-Dependent Type 17 Immune Interactions in Experimental Trauma/Hemorrhagic Shock and Resuscitation Using Computational Modeling

“…We have reported previously that the expression of TLR4 impacts dynamic networks of inflammation induced by LPS in mice ( 14 , 15 ). We therefore hypothesized that the expression of TLR4 impacts the cross-compartment spread of inflammation, and thus compared the dynamic evolution of inflammation in WT and TLR4 -/- mice following T/HS-R.…”

“…A key, unanswered question remains that of how trauma/hemorrhage impact immuno-inflammatory responses in various organs and the systemic circulation. We have recently begun to address this question in the simpler context of experimental endotoxemia in mice, utilizing computational methods aimed at defining the temporal hierarchy of the cross-tissue progression of inflammation, dynamic networks of inflammation, and the hallmarks of pathological systemic spillover of inflammation ( 14 , 15 ). These studies also implicated type 17 immune responses in the spatiotemporal elaboration of inflammation ( 15 ).…”

“…In the context of sepsis, TLR4 transduces signals from pathogen-derived molecular pattern (PAMP) molecules such as endotoxin/lipopolysaccharide (LPS) ( 16 ), whereas in the setting of trauma TLR4 mediates signals from damage-associated molecular pattern (DAMP) molecules such as high-mobility group box-1 (HMGB1) ( 17 ). Our prior studies on modeling the spatiotemporal dynamics of LPS-induced inflammation suggested distinct, tissue- and time-specific differences in wild type (WT) C57BL/6 mice as compared to TLR4-deficient (TLR4 -/- ) mice ( 14 , 15 ).…”

“…We also sought to define the impact of TLR4 deficiency. Our prior data-driven modeling studies in both experimental ( 18 ) and clinical ( 12 , 19 – 21 ) settings of trauma/hemorrhage leveraged Principal Component Analysis (PCA) ( 7 , 18 , 22 ), cross-correlation analysis ( 14 ), and dynamic network discovery algorithms ( 4 , 8 , 15 ). Here, we utilized PCA along with an emerging multi-dimensional network analysis approach known as hypergraphs ( 23 – 26 ) to define novel DAMP/TLR interactions.…”

Intestinal Barrier Function and Immune Homeostasis Are Missing Links in Obesity and Type 2 Diabetes Development

“…In contrast, Dalby et al ( 74 ) showed that deletion of the TLR4 and co-receptor CD14, which are involved in LPS signaling ( 60 , 61 ), did not prevent diet-induced obesity in mice, suggesting that obesity may develop independent of LPS and metabolic endotoxemia. Intriguingly, intestinal permeability and LPS levels were raised in obese TLR4 and CD14 knockout mice ( 74 ), suggesting that LPS could signal through an unidentified TLR4-independent pathway ( 75 ). Importantly, knockout of TLR4 in specific cell populations such as intestinal epithelial cells (IECs) rather than whole-body knockout may be required to induce metabolic effects ( 66 ).…”