Purinergic enzymes on extracellular vesicles: immune modulation on the go

Abstract

An increase in the extracellular concentration of ATP as a consequence of cellular stress or cell death results in the activation of immune cells. To prevent inflammation, extracellular ATP is rapidly metabolized to adenosine, which deploys an anti-inflammatory signaling cascade upon binding to P1 receptors on immune cells. The ectonucleotidases necessary for the degradation of ATP and generation of adenosine are present on the cell membrane of many immune cells, and their expression is tightly regulated under conditions of inflammation. The discovery that extracellular vesicles (EVs) carry purinergic enzyme activity has brought forward the concept of EVs as a new player in immune regulation. Adenosine-generating EVs derived from cancer cells suppress the anti-tumor response, while EVs derived from immune or mesenchymal stem cells contribute to the restoration of homeostasis after infection. Here we will review the existing knowledge on EVs containing purinergic enzymes and molecules, and discuss the relevance of these EVs in immune modulation and their potential for therapy.

Mesenchymal Stem Cells and Purinergic Signaling in Autism Spectrum Disorder: Bridging the Gap between Cell-Based Strategies and Neuro-Immune Modulation

“…One of the limitations of further research is the difficulty of EV isolation (especially exosomes), which is underlain by their small nanometric sizes and heterogeneity of EVs. Only recently has some research data linked the extracellular vesicles with certain aspects of purinergic signaling by having ATP and/or Ado in their lumen, as well as active ectonucleotidases and receptors on the membrane surface [ 117 , 118 ]. The ectonucleotidase activity of CD73 is often present in EVs and even mentioned as an EVs’ surface marker.…”

“…The ectonucleotidase activity of CD73 is often present in EVs and even mentioned as an EVs’ surface marker. The concept of adenosine-generating vesicles released by MSCs and contributing to immunomodulation seems to be a promising therapeutic solution [ 118 ]. However, there is still a lack of information on whether and how nucleotides affect the secretion of extracellular vesicles by MSCs.…”

“…Obtained amounts of Ado were related to added ATP, and the inhibition of CD39 resulted in the inhibition of the whole pathway, which strongly reduced Ado concentration [ 192 ]. The presence of the ecto-enzymes is not only limited to the cellular surface, but they appear on extracellular vesicles as well [ 99 , 118 ]. CD73 activity has been shown on the MSC-derived extracellular vesicles in many studies.…”

“…CD73 activity has been shown on the MSC-derived extracellular vesicles in many studies. On the other hand, CD39 is still to be elucidated as there is a high possibility to find it on the surface of vesicles [ 99 , 118 ]. Migration of extracellular vesicles in diseases with ongoing inflammation has been presented for bone marrow MSCs exosomes that were intranasally applied to mice.…”