Macrophagic Stabilin-1 Restored Disruption of Vascular Integrity Caused by Sepsis
Wonhwa Lee
1
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
2
Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea
,
Seung-Yoon Park
3
Department of Biochemistry, School of Medicine, Dongguk University, Gyeongju, Republic of Korea
,
Youngbum Yoo
2
Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea
,
Soon-Young Kim
4
Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
,
Jung-Eun Kim
4
Department of Molecular Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
,
Shin-Woo Kim
5
Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
,
Young-Kyo Seo
2
Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Deajeon, Republic of Korea
,
Eui Kyun Park
6
Department of Pathology and Regenerative Medicine, School of Dentistry, Kyungpook National University, Daegu, Republic of Korea
,
In-San Kim
7
Biomedical Research Institute, Korea Institute of Science and Technology, Seoul, Republic of Korea
8
KU-KIST Graduate School of Converging Science and Technology, Korea University, Seoul, Republic of Korea
,
Jong-Sup Bae
1
College of Pharmacy, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
› Author AffiliationsFunding This research study was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Government of the Republic of Korea (grant number: HI15C0001), by the Bio & Medical Technology Development Program of the National Research Foundation (NRF) funded by the Ministry of Science & ICT (2017M3A9G8083382), by the National Research Foundation of Korea (NRF) grant funded by the Korean government (NRF-2017R1A5A2015391) and by the Korean government (Ministry of Science, ICT) and the Korea Research Institute of Bioscience and Biotechnology Research Initiative Program (KGM3141824).
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.
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