The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15

Bin Pan; Xiangmin Wang; Shinsuke Kojima; Chie Nishioka; Akihito Yokoyama; Goichi Honda; Kailin Xu; Takayuki Ikezoe

doi:10.1160/TH16-10-0762

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2017; 117(03): 570-579
DOI: 10.1160/TH16-10-0762

Blood Cells, Inflammation and Infection

Schattauer GmbH

The fifth epidermal growth factor like region of thrombomodulin alleviates LPS-induced sepsis through interacting with GPR15

Bin Pan

¹Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China

²Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

³Department of Hematology, Fukushima Medical University, Fukushima, Japan

,

Xiangmin Wang

¹Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China

²Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

³Department of Hematology, Fukushima Medical University, Fukushima, Japan

,

Shinsuke Kojima

²Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

,

Chie Nishioka

²Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

⁴Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

,

Akihito Yokoyama

²Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

,

Goichi Honda

⁵Medical Affairs Department, Asahi Kasei Pharma., Kanda Jinbocho, Chiyoda-ku, Tokyo, Japan

,

Kailin Xu

¹Department of Hematology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, China

,

Takayuki Ikezoe

²Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan

³Department of Hematology, Fukushima Medical University, Fukushima, Japan

› Author Affiliations

Abstract

Summary

Thrombomodulin (TM) exerts cytoprotection via the fifth region of epidermal growth factor (EGF)-like domain of TM (TME5) by interacting with G-protein coupled receptor 15 (GPR15) expressed on cell surface of vascular endothelial cells. TM is also implied to mediate anti-inflammatory functions by unknown mechanism. By applying a lipopolysaccharide (LPS)-induced murine sepsis model, we assessed the role of TME5 in septic inflammation and coagulation. We found that TME5 treatment protected mice in association with ameliorating inflammation and coagulopathy in LPS-induced sepsis. Further study confirmed that TME5 bound GPR15 in vitro. Knock out of GPR15 abolished protective role of TME5 in sepsis model. GPR15 mediated anti-inflammatory function of TME5 through suppression of phosphorylation of IκBα, nuclear translocation of NF-κB and release of pro-inflammatory cytokines in macro-phages (Macs). Knock out of GPR15 resulted in dysregulated immune response of Macs, characterised by excessive expression of pro-inflammatory genes and failing to limit immune response. This study indicates that TME5 exerts anti-inflammatory function through inhibition of NF-κB in a GPR15-dependent manner. The use of TME5 may be a potential therapeutic option for treatment of sepsis.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Thrombomodulin - lipopolysaccharide - sepsis - G-protein coupled receptor 15 - macrophages

Full Text

References

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