[PDF][PDF] Activation of vascular endothelial growth factor receptor-3 in macrophages restrains TLR4-NF-κB signaling and protects against endotoxin shock

Y Zhang, Y Lu, L Ma, X Cao, J Xiao, J Chen, S Jiao… - Immunity, 2014 - cell.com
Y Zhang, Y Lu, L Ma, X Cao, J Xiao, J Chen, S Jiao, Y Gao, C Liu, Z Duan, D Li, Y He, B Wei…
Immunity, 2014cell.com
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 …
Summary
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.
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