The Emerging Role of Small Extracellular Vesicles in Inflammatory Airway Diseases

Abstract

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. By transporting a complex cargo that includes genetic material, proteins, lipids, and signaling molecules, sEVs can alter the state of recipient cells. The role of sEVs in mediating inflammatory processes and responses of the immune system is well-documented, and adds another layer of complexity to our understanding of frequent diseases, including chronic rhinosinusitis (CRS), asthma, chronic obstructive pulmonary disease (COPD), and upper airway infections. In these diseases, two aspects of sEV biology are of particular interest: (1) sEVs might be involved in the etiopathogenesis of inflammatory airway diseases, and might emerge as attractive therapeutic targets, and (2) sEVs might be of diagnostic or prognostic relevance. The purpose of this review is to outline the biological functions of sEVs and their capacity to both augment and attenuate inflammation and immune response in the context of pathogen invasion, CRS, asthma, and COPD.

Keywords: bronchial diseases; chronic rhinosinusitis; exosomes; inflammation; inflammatory airway diseases; lung diseases; otitis media; small extracellular vesicles.

Figure 1

Small extracellular vesicles present in human plasma may be separated using pre-clearing with differential centrifugation and a 200 nm filter (not shown), followed by size exclusion chromatography. The isolated sEVs can be characterized according to the guidelines of the International Society for Extracellular Vesicles [4] with the use of (a) Cryo-EM microscopy (52,000×) to estimate their size and morphology, (b) western blot for two positive (CD63 and CD9) and one negative (Grp94) sEV marker, and (c) nanoparticle tracking analysis (NTA), which allows the evaluation of vesicle size (average diameter = 90.9 nm) and concentration (1.3 × 10¹¹ particles/mL) [9] (modified).

Figure 2

sEVs are carriers of a complex biologically active cargo [27] (modified). The figure presents selected molecules carried within sEVs that are involved in inflammatory airway diseases. The biogenesis of sEVs begins when cargos for secretion are located in early endosomes, (1) which accumulate intraluminal vesicles (2) and later convert to multivesicular bodies (MVBs) (3). MVBs might fuse with lysosomes and degrade (4) or fuse with the plasma membrane, (5) releasing sEVs into the intercellular space.