Abstract
Unconventional secretion and subsequent uptake of molecular cargo via extracellular vesicles (EVs) is an important mechanism by which cells can exert paracrine effects. While this phenomenon has been widely characterized in the context of their ability to promote inflammation, less is known about the ability of EVs to transfer immunosuppressive cargo. Maintenance of normal physiology in the lung requires suppression of potentially damaging inflammatory responses to the myriad of insults to which it is continually exposed. Recently, our laboratory has reported the ability of alveolar macrophages (AMs) to secrete suppressors of cytokine signaling (SOCS) proteins within microvesicles (MVs) and exosomes (Exos). Uptake of these EVs by alveolar epithelial cells (AECs) resulted in inhibition of pro-inflammatory STAT activation in response to cytokines. Moreover, AM packaging of SOCS within EVs could be rapidly tuned in response to exogenous or AEC-derived substances. In this article we will highlight gaps in knowledge regarding microenvironmental modulation of cargo packaging and utilization as well as EV secretion and uptake. Advances in these areas are critical for improving understanding of intercellular communication in the immune system and for therapeutic application of artificial vesicles aimed at treatment of diseases characterized by dysregulated inflammation.
Highlights
Intercellular communication is vital for multicellular organisms to respond and adapt to changes in the environment
suppressors of cytokine signaling (SOCS) proteins had never been identified previously in the extracellular space, we found that alveolar macrophages (AMs) constitutively secrete two distinct SOCS proteins (SOCS1 and SOCS3) within extracellular vesicles (EVs) (Bourdonnay et al, 2015)
The question of how cargo within internalized EVs reaches the compartments within recipient cells in which it can be functionally active remains enigmatic. This challenge is vividly illustrated by the case of SOCS proteins transferred in AM-derived EVs, which must reach the cytosol of recipient alveolar epithelial cells (AECs) in order to effectively inhibit STAT phosphorylation
Summary
Intercellular communication is vital for multicellular organisms to respond and adapt to changes in the environment. It is a cornerstone of the immune response and is classically accomplished via either direct cell-cell contact or secretion of soluble mediators. EVs are small membrane-delimited packets which, by transferring diverse forms of biologically active cargo (lipids, RNA, DNA, soluble and surface proteins) from donor to recipient cells, participate in both homeostasis and disease. EVs comprise a spectrum of structures that vary in size, membranes of origin, mechanisms of release, and surface and internal cargo. MVs originate by direct plasma membrane budding and are ∼100–1000 nm in diameter, while Exos originate from endosomal membranes within multivesicular bodies and are ∼30–150 nm in diameter
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