<i>In vitro</i> cytokine concentrations after <i>in vivo</i> treatment with either saline or LPS in young and middle aged mice.

<p>Young (n = 16) and middle-aged mice (n = 16) were injected with saline or 3 m/kg LPS and peritoneal macrophages were harvested as described in <i>Materials and Methods</i>. Middle-aged mice had significantly higher levels (*<i>P</i><0.001 vs. young mice) of IL-6 (<b>A</b>), TNF-α (<b>B</b>), IL-10 (<b>C</b>) and KC (<b>D</b>) after <i>in vivo</i> treatment with saline followed by <i>in vitro</i> treatment with culture media. IL-6 (<b>A</b>), TNF-α (<b>B</b>), IL-10 (<b>C</b>), KC (<b>D</b>), IL-2 (<b>E</b>), IL-4 (<b>F</b>) and VEGF (<b>G</b>) concentrations were significantly higher (*<i>P</i><0.001 vs. young mice) after <i>in vivo</i> LPS treatment followed by <i>in vitro</i> treatment with culture media.</p

Data and model output for plasma cytokines and NO₂^−/NO₃⁻ in young and middle-aged mice subjected to LPS.

<p>Young (C57BL/6; n = 4 animals per time point) and middle-aged mice (n = 4 per time point) were injected with saline or 3 mg/kg LPS as described in <i>Materials and Methods</i>. Plasma concentration as a function of time and age: (<b>A</b>) IL-6, (<b>B</b>) TNF-α, (<b>C</b>) IL-10 and (<b>D</b>) NO₂^−/NO₃⁻. Symbols represent the mean ± SEM (<i>P</i><0.05, analyzed by Two-way ANOVA followed by Holm-Sidak test for plasma levels of IL-6 and IL-10). For young mice, the line indicates the output of the baseline model of acute inflammation. For middle-aged mice, model re-calibration was carried out as described in the <i>Materials and Methods</i>, yielding five models (colored lines). “Best Model” indicates the model giving the best overall fit to the data.</p

Statistically significant plasma inflammatory mediators in both young and middle-aged mice after I.P saline or LPS treatment.

<p>Young and middle-aged mice (n = 16 each) were treated with either saline or LPS <i>in vivo</i> for 90 min., and circulating inflammatory mediators were assessed as described in <i>Materials and Methods</i>.</p

Difference in plasma cytokines and NO₂^−/NO₃⁻ in young and middle-aged mice subjected to LPS.

<p>Young (C57BL/6; n = 3–8 animals per time point) and middle-aged mice (n = 4 per time point) were injected with saline or 3 mg/kg LPS as described in <i>Materials and Methods</i>. Middle-aged mice had significantly higher levels of IL-6 (<b>A</b>), TNF-α (<b>B</b>), and IL-10(<b>C</b>) at 60 and 90 min when compared to young mice post-LPS treatment (<i>P</i><0.05, analyzed by Two-way ANOVA).</p

Characteristics of middle-aged specific mathematical models of inflammation.

<p>Model parameters (constants) changed in the middle-aged specific models are indicated, along with their biological significance. Param.: parameter. Def.: definition.</p

Total peritoneal cell count and cell viability.

<p>(<b>A</b>): Middle-aged mice that received <i>in vivo</i> LPS had significantly lower (*<i>P</i><0.001) cell count when compared to similarly treated young mice. (<b>B</b>): LPS-treated middle-aged mice had significantly lower (*<i>P</i> = 0.008) cell viability when compared to LPS treated young mice.</p

DataSheet2_Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation.PDF

Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.</p

Table1_Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation.DOCX

Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.</p

DataSheet4_Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation.PDF

Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.</p

DataSheet3_Computational inference of chemokine-mediated roles for the vagus nerve in modulating intra- and inter-tissue inflammation.PDF

Introduction: The vagus nerve innervates multiple organs, but its role in regulating cross-tissue spread of inflammation is as yet unclear. We hypothesized that the vagus nerve may regulate cross-tissue inflammation via modulation of the putatively neurally regulated chemokine IP-10/CXCL10.Methods: Rate-of-change analysis, dynamic network analysis, and dynamic hypergraphs were used to model intra- and inter-tissue trends, respectively, in inflammatory mediators from mice that underwent either vagotomy or sham surgery.Results: This analysis suggested that vagotomy primarily disrupts the cross-tissue attenuation of inflammatory networks involving IP-10 as well as the chemokines MIG/CXCL9 and CCL2/MCP-1 along with the cytokines IFN-γ and IL-6. Computational analysis also suggested that the vagus-dependent rate of expression of IP-10 and MIG/CXCL9 in the spleen impacts the trajectory of chemokine expression in other tissues. Perturbation of this complex system with bacterial lipopolysaccharide (LPS) revealed a vagally regulated role for MIG in the heart. Further, LPS-stimulated expression of IP-10 was inferred to be vagus-independent across all tissues examined while reducing connectivity to IL-6 and MCP-1, a hypothesis supported by Boolean network modeling.Discussion: Together, these studies define novel spatiotemporal dimensions of vagus-regulated acute inflammation.</p