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.
Thromb Haemost. 2018 Oct;118(10):1776-1789. doi: 10.1055/s-0038-1669477. Epub 2018 Sep 20.
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.
脓毒症是由于对细菌感染的过度炎症反应而发展的，它会破坏血管完整性。稳定素-1（STAB-1）是一种吞噬受体，它通过磷脂酰丝氨酸（PS）依赖性方式介导吞噬作用。STAB-1 预计在脓毒症的吞噬作用中发挥重要作用。在这里，我们确定了 STAB-1 在维持和恢复血管完整性方面的作用。使用巨噬细胞和血管内皮细胞来评估 STAB-1 对存活率、吞噬活性、血管通透性和跨内皮迁移（TEM）的影响。此外，我们还研究了高迁移率族蛋白 B1（HMGB1）-晚期糖基化终产物受体复合物是否干扰了 Stab1 与 PS 的结合。与野生型小鼠相比，Stab1 基因敲除小鼠的死亡率更高，并且 STAB-1 缺乏与巨噬细胞介导的吞噬作用减少和血管完整性破坏有关，这会增加血管通透性，并增强 TEM。STAB-1 缺乏会促进肺损伤，并增加脓毒症标志物的表达。外源性应用抗 HMGB1 中和抗体可改善脓毒症中的吞噬作用、血管完整性和存活率。总之，我们的研究结果表明，STAB-1 通过清除感染的凋亡内皮细胞来调节和维持血管完整性。此外，我们的研究结果表明，通过 STAB-1 信号靶向血管完整性的干预措施可能是脓毒症有希望的治疗方法。
