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Thromb Haemost 2015; 114(02): 350-363
DOI: 10.1160/TH14-11-0969
Endothelium and Angiogenesis
Schattauer GmbH

Role of moesin in HMGB1-stimulated severe inflammatory responses

Wonhwa Lee   *
1   College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
2   Department of Biochemistry and Cell Biology, BK21 Plus KNU Biomedical Convergence Program, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
,
Oh Kwang Kwon   *
1   College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
,
Min-Su Han
3   Laboratory for Arthritis and Bone Biology, Fatima Research Institute, Daegu Fatima Hospital, Daegu, Republic of Korea
,
You-Mie Lee
1   College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
,
Shin-Woo Kim
4   Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
,
Kyung-Min Kim
5   Division of Plant Biosciences, School of Applied BioSciences, College of Agriculture and Life Science, Kyungpook National University, Daegu, Republic of Korea
,
Taeho Lee
1   College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
,
Sangkyu Lee
1   College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
,
Jong-Sup Bae
1   College of Pharmacy, CMRI, Research Institute of Pharmaceutical Sciences, Kyungpook National University, Daegu, Republic of Korea
› Author Affiliations
Further Information

Publication History

Received: 23 November 2014

Accepted after major revision: 25 February 2015

Publication Date:
21 November 2017 (online)

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Summary

Sepsis is a life-threatening condition that arises when the body’s response to infection causes systemic inflammation. High-mobility group box 1 (HMGB1), as a late mediator of sepsis, enhances hyper-permeability, and it is therefore a therapeutic target. Despite extensive research into the underlying mechanisms of sepsis, the target molecules controlling vascular leakage remain largely unknown. Moesin is a cytoskeletal protein involved in cytoskeletal changes and para-cellular gap formation. The objectives of this study were to determine the roles of moesin in HMGB1-mediated vascular hyperpermeability and inflammatory responses and to investigate the mechanisms of action underlying these responses. Using siRNA knockdown of moesin expression in primary human umbilical vein endothelial cells (HUVECs), moesin was found to be required in HMGB1-induced F-actin rearrangement, hyperpermeability, and inflammatory responses. The mechanisms involved in moesin phosphorylation were analysed by blocking the binding of the HMGB1 receptor (RAGE) and inhibiting the Rho and MAPK pathways. HMGB1-treated HUVECs exhibited an increase in Thr558 phosphorylation of moesin. Circulating levels of moesin were measured in patients admitted to the intensive care unit with sepsis, severe sepsis, and septic shock; these patients showed significantly higher levels of moesin than healthy controls, which was strongly correlated with disease severity. High blood moesin levels were also observed in cecal ligation and puncture (CLP)-induced sepsis in mice. Administration of blocking moesin antibodies attenuated CLP-induced septic death. Collectively, our findings demonstrate that the HMGB1-RAGE-moesin axis can elicit severe inflammatory responses, suggesting it to be a potential target for the development of diagnostics and therapeutics for sepsis.

Keywords

Moesin - HMGB1 - vascular permeability - sepsis - marker

* First two authors contributed equally to this work.


 

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