Zinc Finger Protein St18 Protects against Septic Death by Inhibiting VEGF-A from Macrophages

Abstract

Zinc finger protein St18 was initially reported as candidate tumor suppressor gene, and also suggested that fibroblast St18 positively regulates NF-kB 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-kB 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.

Deciphering the molecular and cellular atlas of immune cells in septic patients with different bacterial infections

“…High VEGFA expression in macrophages increases vascular permeability, leading to septic death. In contrast, inhibiting VEGF signaling can effectively reduce inflammation and protect mice with sepsis from death [ 60 ]. In conclusion, our study reveals that macrophages in kidney tissue may contribute to sepsis pathology by secreting growth factors and via integrin-mediated signaling.…”

Chemoprevention of esophageal adenocarcinoma in a rat surgical model by a cysteinyl leukotriene receptor‑1 antagonist

“…Macrophages are the main sources of IL-8 and VEGF ( 37 , 38 ). In this study, macrophage infiltration was not influenced by the CysLT1R antagonist despite the significant suppression of IL-8 and VEGF expression.…”

Macrophage orchestration of epithelial and stromal cell homeostasis in the intestine

“…Upon sensing angiogenic signals (such as hypoxia), macrophages migrated to the site of neovessels, secreting proangiogenic cytokines, including NO or varying proteases to either stimulate endothelial cell proliferation or provide a favorable niche for neovessel growth 201 . In colitis, macrophage‐derived VEGF‐A increased disease susceptibility by disrupting endothelium function 203 . On the other hand, IMφ–endothelium interactions were also reported to be protective in colitis.…”

“…201 In colitis, macrophage-derived VEGF-A increased disease susceptibility by disrupting endothelium function. 203 On the other hand, IMφ-endothelium interactions were also reported to be protective in colitis. For example, IMφs were crucial for maintaining the gut homeostasis by preventing the leakage of the vascular endothelium.…”