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

Zinc finger protein St18 was initially reported as candidate tumor suppressor gene, and also suggested that fibroblast St18 positively regulates NF-kappaB 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-kappaB 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.Maruyama et al. report that St18 is a negative regulator of VEGF-A expression in macrophages. Myeloid-specific St18-deficient mice are vulnerable to sepsis accompanied by elevated serum VEGF-A concentrations. St18 binds to Sp1 and attenuates its activity, leading to the suppression of Sp1 target gene VEGF-A.

Source: Current Awareness Service for Health (CASH) - August 5, 2020 Category: Consumer Health News Source Type: news