Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages
Kenta Maruyama,
Hiroyasu Kidoya,
Naoki Takemura,
Erika Sugisawa,
Osamu Takeuchi,
Takeshi Kondo,
Mohammed Mansour Abbas Eid,
Hiroki Tanaka,
Mikaël M. Martino,
Nobuyuki Takakura,
Yasunori Takayama,
Shizuo Akira,
Alexis Vandenbon,
Yutaro Kumagai
Affiliations
Kenta Maruyama
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan; Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Corresponding author
Hiroyasu Kidoya
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Naoki Takemura
Department of Mucosal Immunology, School of Medicine, Chiba University, Chiba 260-8670, Japan
Erika Sugisawa
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Osamu Takeuchi
Laboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
Takeshi Kondo
Department of Biochemistry, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita 15, Nishi 7, Kita-ku, Sapporo, Hokkaido 060-8636, Japan
Mohammed Mansour Abbas Eid
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Hiroki Tanaka
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Mikaël M. Martino
European Molecular Biology Laboratory Australia, Australian Regenerative Medicine Institute, Monash University, Melbourne, VIC 3800, Australia
Nobuyuki Takakura
Department of Signal Transduction, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
Yasunori Takayama
Division of Cell Signaling, Okazaki Institute for Integrative Bioscience (National Institute for Physiological Sciences), National Institutes of Natural Sciences, Aichi 444-8787, Japan; Department of Physiological Sciences, Graduate University for Advanced Studies, Aichi 444-8787, Japan
Shizuo Akira
WPI Immunology Frontier Research Center (IFReC), Osaka University, Osaka 565-0871, Japan
Alexis Vandenbon
Laboratory of Infection and Prevention, Department of Virus Research, Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
Yutaro Kumagai
Biotechnology Research Institute for Drug Discovery, Department of Life Science and Biotechnology, National Institute of Advanced Industrial Science and Technology, Tsukuba, Ibaraki 305-8565, Japan
Summary: Zinc finger protein St18 was initially reported as candidate tumor suppressor gene, and also suggested that fibroblast St18 positively regulates NF-κB activation. Despite the pleiotropic functions of St18, little is known about its roles in macrophages. Here, we report that myeloid St18 is a potent inhibitor of VEGF-A. Mice lacking St18 in myeloid lineages exhibit increased retinal vasculature with enhanced serum VEGF-A concentrations. Despite the normal activation of NF-κB target genes, these mice are highly susceptible to LPS-induced shock, polymicrobial sepsis, and experimental colitis, accompanied by enhanced vascular and intestinal leakage. Pharmacological inhibition of VEGF signaling rescued the high mortality rate of myeloid-specific St18-deficient mice in response to inflammation. Mechanistically, St18 directly binds to Sp1 and attenuates its activity, leading to the suppression of Sp1 target gene VEGF-A. Using mouse genetic and pharmacological models, we reveal myeloid St18 as a critical septic death protector.
