Pathologic function and therapeutic potential of extracellular vesicle miRNA in sepsis

Abstract

Sepsis is a systemic inflammatory response initiated by an infection, which can lead to multi-organ dysfunction. The pathophysiology of sepsis is complex, and treatment options are limited. Traditional antibiotic therapies have shown limitations, such as promoting the emergence of antibiotic-resistant bacteria and disrupting the natural microbiota. Consequently, there is a pressing need to explore diverse therapeutic approaches for sepsis management. Extracellular vesicles, which play a crucial role in cell-to-cell communication, are released by various cell types throughout the body and possess a membrane structure composed of a lipid bilayer. MicroRNAs may be encapsulated within these structures and can be selectively delivered to target recipient cells through the activation of cell surface receptors or via endocytosis and fusion, thereby modulating the biological functions of target cells. The article examines the pathological alterations that happen as sepsis progresses and the biological control of extracellular vesicles and microRNAs in sepsis. This review focuses on the role of extracellular vesicles and their microRNAs on controlling the inflammatory response, macrophage polarization, programmed cell death, endothelial dysfunction, and microcirculatory changes in sepsis. Furthermore, the obstacles encountered by this novel therapy are also examined.

Keywords: diagnosis; endothelial dysfunction; extracellular vesicle; inflammation; microRNA; programmed cell death; sepsis; therapy.

FIGURE 1

Biogenesis and classification of extracellular vesicles. Extracellular vesicle includes exosomes, microvesicles, and apoptotic bodies. Exosomes, are generated within the endosomal system. Early sorting endosomes can invaginate to form multivesicular bodies (MVBs), which contain intraluminal vesicles (ILVs). MVBs can either fuse with lysosomes for degradation or merge with the plasma membrane to release ILVs into the extracellular space. Microvesicles are formed at the cell surface through outward budding of the plasma membrane. When the nucleus is broken, the cell membrane protrudes outwards, wrapping the fragments of the organelles to form apoptotic bodies. (Created with BioRender.com).

FIGURE 2

Biogenesis of miRNA and EV-miRNA sorting mechanism. MiRNAs sort into EVs through five main pathways ① Membrane Protein-Associated Pathway; ② RNA-Binding Protein and Specific Motif Pathway; ③ miRISC-Associated Pathway; ④Associated with Lipid Composition, Structure; ⑤ Specific sequences or modifications at the 3′end of miRNAs. MiRNAs are transported to recipient cells in three ways (1) Transport of miRNAs via extracellular vesicles (2) Transport of miRNAs via RNA-binding proteins (3) Direct transfer to neighbouring cells via gap junctions formed by connexins (Hong et al., 2015). (Created with BioRender.com).

FIGURE 3

Multiple inflammatory signaling pathways.