The Functional Heterogeneity of Neutrophil-Derived Extracellular Vesicles Reflects the Status of the Parent Cell

Abstract

Similar to other cell types, neutrophilic granulocytes also release extracellular vesicles (EVs), mainly medium-sized microvesicles/microparticles. According to published data, authors have reached a consensus on the physical parameters (size, density) and chemical composition (surface proteins, proteomics) of neutrophil-derived EVs. In contrast, there is large diversity and even controversy in the reported functional properties. Part of the discrepancy may be ascribed to differences in the viability of the starting cells, in eliciting factors, in separation techniques and in storage conditions. However, the most recent data from our laboratory prove that the same population of neutrophils is able to generate EVs with different functional properties, transmitting pro-inflammatory or anti-inflammatory effects on neighboring cells. Previously we have shown that Mac-1 integrin is a key factor that switches anti-inflammatory EV generation into pro-inflammatory and antibacterial EV production. This paper reviews current knowledge on the functional alterations initiated by neutrophil-derived EVs, listing their effects according to the triggering agents and target cells. We summarize the presence of neutrophil-derived EVs in pathological processes and their perspectives in diagnostics and therapy. Finally, the functional heterogeneity of differently triggered EVs indicates that neutrophils are capable of producing a broad spectrum of EVs, depending on the environmental conditions prevailing at the time of EV genesis.

Extracellular Vesicles in Innate Immune Cell Programming

“…Neutrophils can release at least two sub-classes of EV, termed: neutrophil derived trails (NDTRS), which are generated by integrin mediated interactions by migrating neutrophils in response to vascular wall forces and neutrophil derived microvesicles (NDMV), which are dependent on the PI3K pathway and released by membrane blebbing following neutrophil activation [41,42]. NDTRS and NDMV share common proteins but differ in their inflammatory and anti-inflammatory functions, respectively [44]. Therefore, we will focus on the role of NDMV in cellular programming (Figure 2).…”

“…NDMV are present in the plasma of healthy individuals and show augmentation in patients with sepsis [43] and chronic obstructive pulmonary disease (COPD) [45]. NDMV reduce reactive oxygen species (ROS) production in neighbouring neutrophils, leading to an anti-inflammatory phenotype [44]. In addition, NDMV target NF-Biomedicines 2021, 9, x FOR PEER REVIEW chronic obstructive pulmonary disease (COPD) [45].…”

“…Bβ activation in macrophages [46]. Inhibited NF-Biomedicines 2021, 9, x FOR PEER REVIEW chronic obstructive pulmonary disease (CO cies (ROS) production in neighbouring neu notype [44]. In addition, NDMV target NFnase 1 (TAK1) and I ϰ Bβ activation in ma to the nucleus limits tumour necrosis facto tophagy in macrophages [40].…”

“…EV derived from quiescent endothelial cells inhibit monocyte activation by transfer of EV-miRNA-10a, which targets NF-Biomedicines 2021, 9, x FOR PEER REVIEW chronic obstructive pulmonary disease (COPD) [45]. NDMV reduce reactive oxygen cies (ROS) production in neighbouring neutrophils, leading to an anti-inflammatory notype [44]. In addition, NDMV target NF-ϰB transforming growth factor β-activate nase 1 (TAK1) and I ϰ Bβ activation in macrophages [46].…”

Extracellular Vesicles and Renal Fibrosis: An Odyssey toward a New Therapeutic Approach

“…As for composition, EVs can carry all types of biomolecules (proteins, RNA, lipids, metabolites) involved in a number of processes such as adhesion, metabolism, signal transduction, membrane fusion, organization and trafficking, etc., in addition to molecules involved in EVs biogenesis [2,8]. The composition of a particular EV population also depends on the type and physiological condition of its cell of origin [22]. Different molecules specific for cell type or physiological states, such as specific surface receptors, enzymes, or cell markers, may be packed into EVs making them useful as liquid biopsies [23].…”