title: 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.
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yanbo
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yao
authors.initials: Y
authors.lastname: Lu
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Li
authors.initials: L
authors.lastname: Ma
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Xudong
authors.initials: X
authors.lastname: Cao
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Xiao
authors.affiliation: The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, China.
authors.forename: Jiexia
authors.initials: J
authors.lastname: Chen
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Shaozhuo
authors.initials: S
authors.lastname: Jiao
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yunzhen
authors.initials: Y
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: National Institute for Viral Disease Control and Prevention, China CDC, Beijing 102206, China.
authors.forename: Zhaojun
authors.initials: Z
authors.lastname: Duan
authors.affiliation: Shanghai Institutes for Biological Sciences, Shanghai 200031, China.
authors.forename: Dangsheng
authors.initials: D
authors.lastname: Li
authors.affiliation: Cyrus Tang Hematology Center, Soochow University, Suzhou 215123, China.
authors.forename: Yulong
authors.initials: Y
authors.lastname: He
authors.affiliation: 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.
authors.forename: Bin
authors.initials: B
authors.lastname: Wei
authors.affiliation: 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.
authors.forename: Hongyan
authors.initials: H
authors.lastname: Wang
mesh_terms: D000818:Animals; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000276:immunology; D004927:Escherichia coli Infections / Q000276:immunology; D006089:Gram-Negative Anaerobic Bacteria / Q000276:immunology*; D007113:Immunity, Innate / Q000235:genetics; D018836:Inflammation Mediators / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015202:Protein Engineering; D017434:Protein Structure, Tertiary / Q000235:genetics; D012480:Salmonella Infections / Q000276:immunology; D012486:Salmonella typhimurium / Q000276:immunology; D012772:Shock, Septic / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000235:genetics / Q000378:metabolism; D051197:Toll-Like Receptor 4 / Q000378:metabolism; D042582:Vascular Endothelial Growth Factor C / Q000276:immunology / Q000378:metabolism; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000235:genetics / Q000378:metabolism*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008070:Lipopolysaccharides; D016328:NF-kappa B; D019869:Phosphatidylinositol 3-Kinases; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051197:Toll-Like Receptor 4; D042582:Vascular Endothelial Growth Factor C; D040321:Vascular Endothelial Growth Factor Receptor-3; C108944:SOCS1 protein, human