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

Molecular Medicine

Richard L. Simmons¹  Ruben Zamora²  Yoram Vodovotz³  Timothy R. Billiar⁴  Sangeeta Chavan⁵  Theodoros Zanos⁵ 

[1] Department of Surgery, University of Pittsburgh, Starzl Biomedical Sciences Tower, 200 Lothrop St., 15213, Pittsburgh, PA, USA;Department of Surgery, University of Pittsburgh, Starzl Biomedical Sciences Tower, 200 Lothrop St., 15213, Pittsburgh, PA, USA;Center for Inflammation and Regeneration Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, 15219, Pittsburgh, PA, USA;Pittsburgh Liver Research Center, University of Pittsburgh, 15261, Pittsburgh, PA, USA;Department of Surgery, University of Pittsburgh, Starzl Biomedical Sciences Tower, 200 Lothrop St., 15213, Pittsburgh, PA, USA;Center for Inflammation and Regeneration Modeling, McGowan Institute for Regenerative Medicine, University of Pittsburgh, 15219, Pittsburgh, PA, USA;Pittsburgh Liver Research Center, University of Pittsburgh, 15261, Pittsburgh, PA, USA;Center for Systems Immunology, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Department of Surgery, University of Pittsburgh, Starzl Biomedical Sciences Tower, 200 Lothrop St., 15213, Pittsburgh, PA, USA;Pittsburgh Liver Research Center, University of Pittsburgh, 15261, Pittsburgh, PA, USA;Institute of Bioelectronic Medicine, The Feinstein Institutes for Medical Research, Manhasset, NY, USA;

关键词: Endotoxemia;    Endotoxin;    Lipopolysaccharide;    TLR4;    Cytokines;    Chemokines;    Dynamic Network Analysis;    Principal Component Analysis;   

DOI  :  10.1186/s10020-021-00333-z

来源: Springer

【 摘 要 】

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.

【 授权许可】

CC BY