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

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3 Citations (Scopus)


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.

Original languageEnglish
Article number107906
Number of pages20
JournalCell Reports
Issue number2
Publication statusPublished - 14 Jul 2020


  • macrophage
  • sepsis
  • Sp1
  • St18
  • VEGF-A

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