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

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.

Retinoic acid receptor agonist Am80 inhibits CXCL2 production from microglial BV-2 cells via attenuation of NF-κB signaling

“…Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) is another important signaling molecule that plays a key role in induction of pro-inflammatory cytokines and chemokines in microglia and macrophages [25,26]. We confirmed that CAPE (10 μM), an inhibitor of NF-κB [27], virtually abolished LPS-induced CXCL2 mRNA expression in BV-2 cells (Fig.…”

Non-Esterified Fatty Acids Over-Activate the TLR2/4-NF-Κb Signaling Pathway to Increase Inflammatory Cytokine Synthesis in Neutrophils from Ketotic Cows

“…Importantly, treatment with NEFAs also induced the over-expression of TLR2 and TLR4 in PMNs. These results obtained The intracellular signals downstream of TLR activation are propagated via the NF-κB pathway, which is an important redox-sensitive and proinflammatory transcription factor that plays a critical role in the regulation of a variety of genes involved in the inflammatory response [26]. The most classical NF-κB binding form is p65, which remains associated with the IκB family of inhibitory proteins in the cytoplasm before activation [27].…”

Carbohydrate-binding protein CLEC14A regulates VEGFR-2– and VEGFR-3–dependent signals during angiogenesis and lymphangiogenesis

“…Distinct phosphorylation of ERK by CLEC14A modulation upon stimula-deletion of Clec14a, increased vessel density following severe hemorrhaging appears more reliable. While the greater hemorrhagic potential of tumors in CLEC14A-KO mice is a possible cause of early death, we cannot exclude other potential causes, such as the inflammatory response to hemorrhagic shock or B16BL6 cell infiltration of the lungs (Figure 5Q), particularly since both VEGFR-3 and the CLEC14A paralog thrombomodulin regulate sepsis (52)(53)(54). Further immunological analysis of CLEC14A-deficient mice is required to determine the precise cause of early death.…”