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

Abstract

Extracellular vesicles (EVs) in the plasma mediate important inter-cellular communications in the pathogenesis of cancer and inflammatory diseases. EVs express integrins that regulate target specificities and programed cell-1 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.

Exosomal PD-L1: New Insights Into Tumor Immune Escape Mechanisms and Therapeutic Strategies

“…It is worth mentioning that proteolytic degradation or alternative splice variants also produce soluble PD-L2, which may be a complementary biomarker ( He et al, 2004 ; Dai et al, 2014 ; Fukasawa et al, 2017 ; Costantini et al, 2018 ; Buderath et al, 2019 ; Wang Q. et al, 2019 ). Recently, a pilot study found PD-L2-expressing EVs in a murine sepsis model ( Kawamoto et al, 2019 ). Moreover, sepsis patients displayed higher PD-L2 expression on EVs compared with healthy subjects ( Kawamoto et al, 2019 ).…”

“…Recently, a pilot study found PD-L2-expressing EVs in a murine sepsis model ( Kawamoto et al, 2019 ). Moreover, sepsis patients displayed higher PD-L2 expression on EVs compared with healthy subjects ( Kawamoto et al, 2019 ). Additionally, reduced exosomal PD-L2 was observed in IL-10-treated murine dendritic cells ( Ruffner et al, 2009 ).…”

Connexins and Integrins in Exosomes

“…We have studied the levels of integrin expression on exosomes in the plasma of sepsis patients admitted to an ICU (Intensive Care Unit) [62]. Sepsis is a type of life-threatening generalized inflammation induced by aberrantly activated immune responses to infection [63].…”

“…Sepsis is a type of life-threatening generalized inflammation induced by aberrantly activated immune responses to infection [63]. Whereas the exosomal expression levels of β1 and β3 integrins were comparable between sepsis patients and healthy subjects, that of β2 integrin was significantly increased in sepsis patients [62]. In addition, levels of exosomal β2 integrin expression in sepsis patients correlated well with the severity of circulatory collapse and kidney failure.…”

“…In addition, levels of exosomal β2 integrin expression in sepsis patients correlated well with the severity of circulatory collapse and kidney failure. As β2 integrins are only expressed in leukocytes, increased exosomal β2 integrin expression is thought to reflect the enhanced systemic activation of leukocytes, which could lead to inflammatory tissue injury [62].…”