Extracellular Vesicles as Markers and Mediators in Sepsis

Abstract

Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. It remains a highly lethal condition in which current tools for early diagnosis and therapeutic decision-making are far from ideal. Extracellular vesicles (EVs), 30 nm to several micrometers in size, are released from cells upon activation and apoptosis and express membrane epitopes specific for their parental cells. Since their discovery two decades ago, their role as biomarkers and mediators in various diseases has been intensively studied. However, their potential importance in the sepsis syndrome has gained attention only recently. Sepsis and EVs are both complex fields in which standardization has long been overdue. In this review, several topics are discussed. First, we review current studies on EVs in septic patients with emphasis on their variable quality and clinical utility. Second, we discuss the diagnostic and therapeutic potential of EVs as well as their role as facilitators of cell communication via micro RNA and the relevance of micro-organism-derived EVs. Third, we give an overview over the potential beneficial but also detrimental roles of EVs in sepsis. Finally, we focus on the role of EVs in selected intensive care scenarios such as coagulopathy, mechanical ventilation and blood transfusion. Overall, the prospect for EV use in septic patients is bright, ranging from rapid and precise (point-of-care) diagnostics, prevention of harmful iatrogenic interventions, to using EVs as guides of individualized therapy. Before the above is achieved, however, the EV research field requires reliable standardization of the current methods and development of new analytical procedures that can close the existing technological gaps.

Keywords: exosomes; inflammation; microparticles; point-of-care; sepsis.

Figure 1

Release mechanisms and the extracellular vesicle pool. EVs constitute a dynamic pool with a considerable range in size. The classic term microparticles (100-1000 nm, intermediate size range) contains the EV fraction that is sometimes referred to as microvesicles or ectosomes and is released from the cell surface in response to activation (B). Although larger, apoptotic bodies that emerge during the disintegration of dying cells well range into the size spectrum of apoptotic microparticles, making it impossible to distinguish the underlying biogenesis solely based on dimensions (C). Exosomes emerge from the endosomal network and are considered the smallest fraction of the EV pool. Undergoing active packaging processes, exosomes are eventually liberated by the fusion of the multivesicular body with the surface membrane (A).

Figure 2

Prototypic vesicle. Although extracellular vesicles differ in size, composition and biogenesis, some basic characteristics can be summarized: Irrespective of the dimensions, EVs represent spherical, subcellular compartments that are composed of a phospholipid bilayer and various membrane-bound or plasmatic cargo molecules. Depending on the process during which they are released, the EV membrane retains the pattern of the cell surface they originated from. Given that EVs are released from all known tissue types, the maintained transmembrane molecules and phospholipids interact with countless cellular processes. The smaller EV fraction (which arises from the early endosome) and the multivesicular bodies display membrane features that resemble these cell organelles but are subject to fine-tuned wrapping mechanisms. In general, the EV content includes proteins/peptides, smaller metabolites, as well as nucleotide sequences.

Figure 3

Modes of interaction of EVs with receiver cells. EVs represent cellular shuttles that are capable of transferring a variety of compounds between cells. (A) Upon fusion, vesicles rapidly modify the membrane composition of the receiver cell by transferring phospholipids and transmembrane molecules. (B) Meanwhile, a variety of cargo molecules are directly ejected into the plasma of the cell. Compounds like growth factors, cytokines or other mediators are able to provoke an immediate metabolic response and to directly interfere with the receiver cell's signal transduction. (C) During states of systemic inflammation and cell activation, tissue factor and phosphatidylserine-bearing vesicles represent microcarriers for the dissemination of a procoagulant phenotype. (D) Any component of the vesicle membrane can function as a ligand for receptors at the surface of the receiver cell, thereby triggering a multitude of responses. (E) During endocytosis, vesicles retain their membrane integrity and are engulfed by invagination. (F) Aside from proteins and metabolites that directly provoke the transduction of signals, other content like micro ribonucleic acids (RNA) are capable of silencing the expression of genes. (G) By altering the posttranscriptional processing on a messenger RNA level, this interference not only affects the synthesis of signaling molecules but secondarily also the expression of transcription factors. (H) Finally, EVs also play a role in fundamental mechanisms of immunity, including cytokine synthesis and antigen presentation.