Abstract
Cytokines and extracellular vesicles are two methods of initiating and maintaining cellular crosstalk. The role of cytokines in the initiation, progression, and resolution of inflammation has been well studied and more so, their pathophysiological role in the development of autoimmune disease. In recent years, the impact of extracellular vesicles on the progression of autoimmunity has become more widely appreciated. In this review, we discuss the mechanisms that allow extracellular vesicles of various sources to modulate cytokine production, and release, and how extracellular vesicles might be involved in the direct delivery and modulation of cytokine levels. Moreover, we explore what challenges are faced by current therapies and the promising future for extracellular vesicles as therapeutic agents in conditions driven by immune dysregulation.
Highlights
Secreted, soluble factors such as hormones, growth factors, and cytokines are key drivers of cellular communication
The initial release of pro-inflammatory cytokines, such as tumour necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β), by tissue-resident cells induces the expression of adhesion molecules, such as selectins and integrins, which facilitates immune cell recruitment [10]
Circulating IL-37 is increased in patients with systemic lupus erythematosus (SLE), and it is thought that this reflects an IL-1/IL-37 negative feedback loop in the context of mast cell insensitivity to IL-37 [35]
Summary
EVs were initially discovered as platelet-derived particles with prothrombotic properties and aptly named “platelet dust”. Not all intraluminal vesicles are destined to be released as exosomes, as some multivesicular bodies may fuse with lysosomes and undergo destruction [46] This process can occur in endosomal sorting complexes required for transport (ESCRT) either in a dependent or independent manner, the latter being dependent on ceramide and to an extent, tetraspanin expression [47]. Increased intracellular calcium triggers a cascade of enzymes and G-protein-coupled receptors, which triggers phosphatidyl serine flipping from inside the cell to the outside, cellular depolarization, and cytoskeletal contraction [49,50]. These processes result in the outwards blebbing and pinching of the phospholipid bilayer releasing microvesicles into the extracellular space [51]. Hothweerveelar,tiaosnswhiipthbmetwosetenmEeVdisaatnodrsinofflacmelmlualatironcoismamlsouninictiamtiaotnelsy, tlihnekerdelawtiitohntshheippabthetowgeeneinc rEoVlesoafnd inflEaVms mduartiinogn aisutaolismo minutinmitayte[6ly7]l.inked with the pathogenic role of EVs during autoimmunity [67]
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