Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages
Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages
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DOI：
10.1016/j.celrep.2020.107906
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发表时间：
2020-07-14
期刊：
影响因子：
8.8
通讯作者：
Kumagai, Yutaro
中科院分区：
文献类型：
--
作者：
Maruyama, Kenta;Kidoya, Hiroyasu;Kumagai, Yutaro
锌指蛋白St18最初被报道为候选肿瘤抑制基因，并且也表明成纤维细胞St18正向调节核因子 - κB的激活。尽管St18具有多效性功能，但对其在巨噬细胞中的作用知之甚少。在此，我们报道髓系St18是血管内皮生长因子 - A（VEGF - A）的一种强效抑制剂。髓系细胞谱系中缺乏St18的小鼠表现出视网膜血管增多，血清VEGF - A浓度升高。尽管核因子 - κB靶基因正常激活，但这些小鼠对脂多糖诱导的休克、多微生物败血症和实验性结肠炎高度敏感，并伴有血管和肠道渗漏增加。对VEGF信号通路的药理抑制挽救了髓系特异性St18缺陷小鼠在炎症反应中的高死亡率。从机制上讲，St18直接与Sp1结合并减弱其活性，从而导致Sp1靶基因VEGF - A的抑制。通过使用小鼠遗传学和药理学模型，我们揭示了髓系St18是一种关键的败血症死亡保护因子。
Zinc finger protein St18 was initially reported as candidate tumor suppressor gene, and also suggested that fibroblast St18 positively regulates NF-kappa B 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-kappa B 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.