Thromb Haemost. 2018 Oct;118(10):1776-1789. doi: 10.1055/s-0038-1669477. Epub 2018 Sep 20.
Lee, W; Park, SY; Yoo, Y; Kim, SY; Kim, JE; Kim, SW; Seo, YK; Park, EK; Kim, IS; Bae, JS
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea. Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea. Department of Biochemistry, School of Medicine, Dongguk University, Gyeongju, Republic of Korea. Department of Internal Medicine, Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea. Department of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea. Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea. KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea.
Sepsis develops because of overwhelming inflammatory responses to bacterial infection, and disrupts vascular integrity. Stabilin-1 (STAB-1) is a phagocytic receptor, which mediates efferocytosis in a phosphatidylserine (PS)-dependent manner. STAB-1 is expected to play important roles in efferocytosis during sepsis. Here, we determined the role of STAB-1 in maintaining and restoring vascular integrity. Macrophages and vascular endothelial cells were used to assess the effect of STAB-1 on survival rate, phagocytic activity, vascular permeability and transendothelial migration (TEM). Additionally, we investigated whether the high-mobility group box 1 (HMGB1)-receptor for advanced glycated end products complex interfered with the binding of Stab1 to PS. Mortality rate was higher in the Stab1-knockout mice than in the wild-type mice, and STAB-1 deficiency was related to reduced macrophage-mediated efferocytosis and the disruption of vascular integrity, which increased vascular permeability, and enhanced TEM. STAB-1 deficiency promoted lung injury, and elevated the expression of sepsis markers. The exogenous application of the anti-HMGB1 neutralizing antibody improved efferocytosis, vascular integrity and survival rate in sepsis. Collectively, our findings indicated that STAB-1 regulated and maintained vascular integrity through the clearance of infected apoptotic endothelial cells. Moreover, our results suggested that interventions targeting vascular integrity by STAB-1 signalling are promising therapeutic approaches to sepsis.
The team at Ozgene has over two decades of experience creating customised knockout and knock-in mice for pivotal medical research globally. Over 400 scientific publications are based on research using Ozgene mice.