Abstract
Toll-like receptors (TLRs) are critical in mediating innate immune responses against infections. However, uncontrolled TLR-triggered inflammation is associated with endotoxin shock. To better understand the homeostatic mechanisms induced by TLR4 signaling, we screened a group of key cytokines, chemokines, growth factors, and their receptors for bacteria- or LPS-induced expression. The surface vascular endothelial growth factor receptor-3 (VEGFR-3) and its ligand VEGF-C were upregulated in macrophages. VEGFR-3 ligation by VEGF-C significantly attenuated proinflammatory cytokine production. Notably, ablation of the ligand-binding domain or tyrosine kinase activity of VEGFR-3 rendered mice more sensitive to septic shock. VEGFR-3 restrained TLR4-NF-κB activation by regulating the PI3-kinase-Akt signaling pathway and SOCS1 expression. Aside from targeting lymphatic vessels, we suggest a key role of VEGFR-3 on macrophages to prevent infections that is complicated with lymphoedema. Thus, VEGFR-3-VEGF-C signaling represents a "self-control" mechanism during antibacterial innate immunity.
Copyright © 2014 Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cytokines / metabolism
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Disease Models, Animal
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Escherichia coli / immunology
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Escherichia coli Infections / immunology
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Gram-Negative Anaerobic Bacteria / immunology*
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Immunity, Innate / genetics
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Inflammation Mediators / metabolism
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Lipopolysaccharides / immunology
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Macrophages / immunology*
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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NF-kappa B / metabolism
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Phosphatidylinositol 3-Kinases / metabolism
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Protein Engineering
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Protein Structure, Tertiary / genetics
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Salmonella Infections / immunology
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Salmonella typhimurium / immunology
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Shock, Septic / immunology*
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Signal Transduction / immunology
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins / genetics
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Suppressor of Cytokine Signaling Proteins / metabolism
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Toll-Like Receptor 4 / metabolism
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Vascular Endothelial Growth Factor C / immunology
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Vascular Endothelial Growth Factor C / metabolism
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Vascular Endothelial Growth Factor Receptor-3 / genetics
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Vascular Endothelial Growth Factor Receptor-3 / metabolism*
Substances
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Cytokines
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Inflammation Mediators
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Lipopolysaccharides
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NF-kappa B
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SOCS1 protein, human
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Suppressor of Cytokine Signaling 1 Protein
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Suppressor of Cytokine Signaling Proteins
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Toll-Like Receptor 4
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Vascular Endothelial Growth Factor C
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Vascular Endothelial Growth Factor Receptor-3