Study of osteo-nociceptive-immune system

2020 Fiscal Year Final Research Report

• Project/Area Number: 18H02970
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Review Section: Basic Section 57020:Oral pathobiological science-related
• Research Institution: National Institute for Physiological Sciences (2019-2020); Osaka University (2018)
• Principal Investigator: Maruyama Kenta 生理学研究所, 生体機能調節研究領域, 特別協力研究員 (60724119)
• Project Period (FY): 2018-04-01 – 2021-03-31
• Keywords: 敗血症 / 血管新生 / 血管透過性 / VEGF / St18

Outline of Final Research Achievements

St18 was initially reported as candidate tumor suppressor gene. 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.

Free Research Field

老年内科学

Academic Significance and Societal Importance of the Research Achievements

本研究によって、St18がVEGFの抑制因子であることが判明した。St18の発現を誘導することのできる化合物を発見できた場合には、VEGFのかかわる様々な疾患（敗血症、癌、糖尿病網膜症) の治療が可能となる。