Spatiotemporally specific roles of TLR4, TNF, and IL-17A in murine endotoxin-induced inflammation inferred from analysis of dynamic networks.
Animals
Biomarkers
Computational Biology
/ methods
Cytokines
/ metabolism
Disease Models, Animal
Disease Susceptibility
Endotoxins
/ adverse effects
Inflammation
/ etiology
Inflammation Mediators
/ metabolism
Interleukin-17
/ genetics
Male
Mice
Mice, Transgenic
Toll-Like Receptor 4
/ genetics
Tumor Necrosis Factor-alpha
/ genetics
Chemokines
Cytokines
Dynamic Network Analysis
Endotoxemia
Endotoxin
Lipopolysaccharide
Principal Component Analysis
TLR4
Journal
Molecular medicine (Cambridge, Mass.)
ISSN: 1528-3658
Titre abrégé: Mol Med
Pays: England
ID NLM: 9501023
Informations de publication
Date de publication:
24 06 2021
24 06 2021
Historique:
received:
05
04
2021
accepted:
19
06
2021
entrez:
25
6
2021
pubmed:
26
6
2021
medline:
13
1
2022
Statut:
epublish
Résumé
Bacterial lipopolysaccharide (LPS) induces a multi-organ, Toll-like receptor 4 (TLR4)-dependent acute inflammatory response. 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. 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. We have derived novel, systems-level insights regarding the spatiotemporal evolution acute inflammation.
Sections du résumé
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.
Identifiants
pubmed: 34167455
doi: 10.1186/s10020-021-00333-z
pii: 10.1186/s10020-021-00333-z
pmc: PMC8223370
doi:
Substances chimiques
Biomarkers
0
Cytokines
0
Endotoxins
0
Inflammation Mediators
0
Interleukin-17
0
Toll-Like Receptor 4
0
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
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