Extracellular Vesicles (EVs) as Crucial Mediators of Cell-Cell Interaction in Asthma

Abstract

Asthma is the most common chronic respiratory disorder worldwide and accounts for a huge health and economic burden. Its incidence is rapidly increasing but, in parallel, novel personalized approaches have emerged. Indeed, the improved knowledge of cells and molecules mediating asthma pathogenesis has led to the development of targeted therapies that significantly increased our ability to treat asthma patients, especially in severe stages of disease. In such complex scenarios, extracellular vesicles (EVs i.e., anucleated particles transporting nucleic acids, cytokines, and lipids) have gained the spotlight, being considered key sensors and mediators of the mechanisms controlling cell-to-cell interplay. We will herein first revise the existing evidence, mainly by mechanistic studies in vitro and in animal models, that EV content and release is strongly influenced by the specific triggers of asthma. Current studies indicate that EVs are released by potentially all cell subtypes in the asthmatic airways, particularly by bronchial epithelial cells (with different cargoes in the apical and basolateral side) and inflammatory cells. Such studies largely suggest a pro-inflammatory and pro-remodelling role of EVs, whereas a minority of reports indicate protective effects, particularly by mesenchymal cells. The co-existence of several confounding factors-including technical pitfalls and host and environmental confounders-is still a major challenge in human studies. Technical standardization in isolating EVs from different body fluids and careful selection of patients will provide the basis for obtaining reliable results and extend their application as effective biomarkers in asthma.

Keywords: airway inflammation; endotypes; microRNA (miRNA); signaling.

Figure 1

The main pathological hallmarks of remodeling in asthma encompass alterations in different airway compartments: Airway epithelium (epithelial shedding, mucous cell metaplasia); subepithelial basement membrane (collagen deposition and thickening of the reticular layer); blood vessels (neoangiogenesis); and airway smooth muscle (enlargement due to hypertrophy/hyperplasia).

Figure 2

Epithelial cells have the potential to release extracellular vesicles with different sizes, origins, and cargoes. Within the endosomal system, internalized cargoes are sorted into early endosomes that then mature into multivesicular bodies (MVB). Cargoes are also delivered from the trans-Golgi network (G) and from the cytosol. Multivesicular bodies cargoes get transported to the plasma membrane, fuse with the cell surface, and are secreted in the extracellular space as exosomes. At variance, microvesicles refer to vesicles generated via direct outward blebbing and pinching of the plasma membrane, a phenomenon accompanied by distinct, localized changes in plasma membrane protein and lipid components that will result in alteration of the membrane curvature and rigidity. Finally, cells that undergo apoptosis go through membrane blebbing and disintegration of the cellular content, which will produce apoptotic bodies. ER: endoplasmic reticulum; N: nucleus; L: lysosome.