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Integrin and PD-1 Ligand Expression on Circulating Extracellular Vesicles in Systemic Inflammatory Response Syndrome and Sepsis

Kawamoto, Eiji*,†; Masui-Ito, Asami*,†; Eguchi, Akiko; Soe, Zay Yar*; Prajuabjinda, Onmanee*; Darkwah, Samuel*; Park, Eun Jeong*; Imai, Hiroshi; Shimaoka, Motomu*

doi: 10.1097/SHK.0000000000001228
Clinical Science Aspects

ABSTRACT Extracellular vesicles (EVs) in the plasma mediate important intercellular communications in the pathogenesis of cancer and inflammatory diseases. EVs express integrins that regulate target specificities and programmed cell death ligand 1 and 2 (PD-L1 and 2) that suppress lymphocyte activation. However, the roles of these molecules on EVs in systemic inflammatory response syndrome (SIRS) and sepsis remain little understood. This study aimed to investigate how the EV expression of integrins and PD-1 ligands might differ in SIRS and sepsis, compared with healthy controls, and to correlate their expression with the clinical parameters reflecting pathogenesis. Twenty-seven SIRS patients without sepsis, 27 sepsis patients, and 18 healthy volunteers were included. EVs were isolated from plasma samples. The expression of three major integrins (β1, β2, β3 integrins) and PD-L1 and 2 were measured. The EV expression of β2 integrin and PD-L2 was significantly increased in sepsis patients compared with healthy controls. EV expression of PD-L1 was not elevated in sepsis and SIRS; however, circulating soluble PD-L1 levels were significantly higher in sepsis. Furthermore, EV expression of β2 integrin in sepsis patients correlated with hypotension and reduced kidney function. In addition, soluble PD-L1 levels correlated with sepsis severity, impaired kidney function, and impaired central nervous system function. These results suggest the potential involvements of the EV β2 integrin, as well as EV PD-L2 and soluble PD-L1, in the septic pathogenesis that occurs with the systemic immune activation leading to multiple organ dysfunctions.

*Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University Graduate School of Medicine, Tsu-City, Mie, Japan

Department of Emergency and Disaster Medicine, Mie University Graduate School of Medicine, Tsu-City, Mie, Japan

Department of Gastroenterology and Hepatology, Mie University Graduate School of Medicine, Tsu-City, Mie, Japan

Address reprint requests to Motomu Shimaoka, MD, PhD, Department of Molecular Pathobiology and Cell Adhesion Biology, Mie University, Graduate School of Medicine, 2-174 Edobashi, Tsu-City, Mie 514-8507, Japan. E-mail:

Received 29 May, 2018

Revised 12 June, 2018

Accepted 8 July, 2018

Funding: This work was supported by JSPS KAKENHI (Grants-in-Aid for Scientific Research) (E.K., A.M.-I., A.E., E.J.P., M.S.) and a research grant from Asahi Kasei Pharma (E.K., M.S.).

The authors report no conflicts of interest.

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