An Updated View of the Importance of Vesicular Trafficking and Transport and Their Role in Immune-Mediated Diseases: Potential Therapeutic Interventions

Abstract

Cellular trafficking is the set of processes of distributing different macromolecules by the cell. This process is highly regulated in cells, involving a system of organelles (endomembranous system), among which are a great variety of vesicles that can be secreted from the cell, giving rise to different types of extracellular vesicles (EVs) that can be captured by other cells to modulate their function. The cells of the immune system are especially sensitive to this cellular traffic, producing and releasing different classes of EVs, especially in disease states. There is growing interest in this field due to the therapeutic and translational possibilities it offers. Different ways of taking advantage of the understanding of cell trafficking and EVs are being investigated, and their use as biomarkers or therapeutic targets is being investigated. The objective of this review is to collect the latest results and knowledge in this area with a specific focus on immune-mediated diseases. Although some promising results have been obtained, further knowledge is still needed, at both the basic and translational levels, to understand and modulate cellular traffic and EVs for better clinical management of these patients.

Keywords: cellular traffic; exosomes; extracellular vesicles; immune-mediated diseases; therapeutic applications.

Figure 1

Summary of the main parties involved in cellular and vesicular traffic. There is communication between the ER and the GA, where the vesicles are packed and classified, transporting different contents in both directions (anterograde and retrograde transport). Some of these vesicles are sent to the plasma membrane to be secreted by a process of constitutive or regulated exocytosis (mainly mediated by the SNARE complex). By endocytosis, different vesicles and substances from the medium are captured, entering the cell and forming the early endosome. The early endosome can recycle these components back to the cell exterior, send them to the GA, or give rise to a secondary endosome, also called multivesicular bodies (MVBs), as this structure contains multiple smaller vesicles known as intraluminal vesicles (ILVs). There is important communication between the GA and MVBs, yielding a bidirectional exchange of vesicles that can be secreted, giving rise to exosomes or becoming part of lysosomes for their subsequent degradation. Likewise, other types of extracellular vesicles, ectosomes or microvesicles (MVs), can be formed directly from the plasma membrane. It is noteworthy that each vesicle can have very diverse contents, including different types of proteins, lipids, and nucleic acids.

Figure 2

Overall summary of the therapeutic strategies currently pursued to limit the influence of high cellular traffic, production, release, and uptake in the IS. There are different approaches aimed at cell trafficking and its organelles, as well as at EVs, with some promising but still preclinical results. On the other hand, researchers are also beginning to design EVs that can be used for therapeutic purposes. In these cases, it is important to try to ensure their specificity and avoid their elimination by cells of the IS, so the selection of their membrane components should be oriented to this end. In the same way, modulating their contents and even adding a specific therapeutic agent could bring multiple benefits to the clinical management of IMIDs. For this, different approaches are being evaluated, such as modifying their content before their production (at the cellular level) or after being released by the cells, through chemical modifications.