Macrophagic Stabilin-1 Restored Disruption of Vascular Integrity Caused by Sepsis

Wonhwa Lee; Seung-Yoon Park; Youngbum Yoo; Soon-Young Kim; Jung-Eun Kim; Shin-Woo Kim; Young-Kyo Seo; Eui Kyun Park; In-San Kim; Jong-Sup Bae

doi:10.1055/s-0038-1669477

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2018; 118(10): 1776-1789
DOI: 10.1055/s-0038-1669477

Blood Cells, Inflammation and Infection

Georg Thieme Verlag KG Stuttgart · New York

Macrophagic Stabilin-1 Restored Disruption of Vascular Integrity Caused by Sepsis

Wonhwa Lee

¹College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

²Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea

,

Seung-Yoon Park

³Department of Biochemistry, School of Medicine, Dongguk University, Gyeongju, Republic of Korea

,

Youngbum Yoo

²Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea

,

Soon-Young Kim

⁴Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

,

Jung-Eun Kim

⁴Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

,

Shin-Woo Kim

⁵Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea

,

Young-Kyo Seo

²Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea

,

Eui Kyun Park

⁶Department of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea

,

In-San Kim

⁷Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea

⁸KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea

,

Jong-Sup Bae

¹College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea

› Author Affiliations

Abstract

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.

Keywords

STAB-1 - efferocytosis - sepsis - vascular integrity - phagocytosis

Full Text

References

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Supplementary Material