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. 2021 Feb 3;11:619458. doi: 10.3389/fphar.2020.619458

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Copyright © 2021 Giuliani, Sarti and Di Virgilio.

This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

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Schematic exemplification of purinergic receptor/ectonucleotidase cooperation in the activation/inhibition of the innate immune response. (A) ATP released via pannexin-1 (panx-1) from human neutrophils exposed to inflammatory stimuli triggers IL-8 production acting at the P2Y2R. NTPDase1/CD39 and NT5E/CD73 sequentially degrade extracellular ATP and limit neutrophil recruitment. (B) Extracellular nucleotides, firstly ATP, acting at the P2X7R, promote monocyte recruitment, modulate phagocytosis and support NLRP3 inflammasome-mediated IL-1β release. NTPDase1/CD39 and NT5E/CD73, expressed to high level on the macrophage plasma membrane, generate adenosine (ADO) and support a feed-back regulatory mechanism. Adenosine-mediated P1R stimulation generates an anti-inflammatory environment characterized by down-modulation of inflammatory cytokines release and enhanced secretion of anti-inflammatory cytokines and growth factors. This balance can be tilted towards an activated state, e.g., to support a more vigorous adaptive immune response, by IFN-γ, a stimulus that makes macrophages less sensitive to adenosine inhibition.