Cell Reports
Volume 32, Issue 2, 14 July 2020, 107906
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Article
Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages

https://doi.org/10.1016/j.celrep.2020.107906Get rights and content
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Highlights

  • Myeloid-specific St18-deficient mice are vulnerable to polymicrobial sepsis

  • Myeloid St18 is dispensable for the activation of NF-κB target genes

  • St18-deficient macrophages produce robust amounts of VEGF-A

  • St18 attenuates Sp1 activity, leading to the suppression of VEGF-A

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.

Keywords

St18
sepsis
VEGF-A
Sp1
macrophage

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Present address: Clinical Pathology Department, Faculty of Medicine, Fayoum University, Fayoum University Hospitals, Fayoum City, P.O. 63514 Egypt

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