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Immunity. 2014 Apr 17;40(4):501-14. doi: 10.1016/j.immuni.2014.01.013. Epub 2014 Mar 20.

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

Author information

1
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
2
Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
3
The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
4
National Institute for Viral Disease Control and Prevention, China CDC, Beijing 102206, China.
5
Shanghai Institutes for Biological Sciences, Shanghai 200031, China.
6
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: binweiwhy@gmail.com.
7
State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China; Cancer Research Center, Xu-Hui Central Hospital, Shanghai Clinical Center, Chinese Academy of Sciences, Shanghai 200031, China. Electronic address: hongyanwang@sibcb.ac.cn.

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.

PMID:
24656836
DOI:
10.1016/j.immuni.2014.01.013
[Indexed for MEDLINE]
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