Activation of Vascular Endothelial Growth Factor Receptor-3 in Macrophages Restrains TLR4-NF-κB Signaling and Protects against Endotoxin Shock

• VEGFR-3 and VEGF-C are elevated in TLR4- or Gram− bacterial-challenged macrophages
• VEGF-C ligation of VEGFR-3 inhibits production of proinflammatory cytokines
• VEGFR-3 binds p85α and activates PI3K-Akt1 to dampen TLR4-NF-κB signaling
• VEGFR-3 mutant mice are more sensitive to septic shock

SummaryToll-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.