P2 receptors and extracellular ATP: a novel homeostatic pathway in inflammation

Abstract

Inflammation is an important homeostatic response, which is managed by a complex network of interrelated pathways that determine the level, intensity and localization of inflammation. We now know that purinergic signalling is one of the pathways influencing the initiation, progression and down-modulation of the inflammatory response. Here, we review recent evidence on the role in inflammation of the purinergic signalling system, which is comprised of extracellular ATP, P2 receptors and ecto-enzyme cascades. Recent animal studies with a newly developed bioluminescent ATP probe (pmeLUC), enabling measurement of pericellular ATP in situ, have provided proof that ATP is present in inflamed tissues in vivo at extracellular concentrations sufficient for P2 receptor activation. Increased extracellular ATP levels amplify inflammation in vivo by promoting leukocyte recruitment and NALP3-inflammasome activation via P2X7. Lowering extracellular ATP levels in inflamed tissues, for instance by stimulating its breakdown, inhibits the inflammatory response in vivo. In view of its important role in inflammation, the purinergic signalling system is bound to yield novel therapeutic opportunities for the treatment of inflammatory diseases.

Transfusion-Related Acute Lung Injury: The Work of DAMPs*

“…There is increasing evidence suggesting a role in inflammation of the purinergic signaling system, which includes the action of eATP and P2 receptors [97]. In fact, recent animal studies have provided convincing evidence indicating that ATP is present in inflamed tissues in vivo at extracellular concentrations sufficient for P2 receptor activation.…”

“…In fact, recent animal studies have provided convincing evidence indicating that ATP is present in inflamed tissues in vivo at extracellular concentrations sufficient for P2 receptor activation. Increased eATP levels amplify inflammation in vivo by promoting leukocyte recruitment and, as mentioned above, by NLRP3-inflammasome activation via P2X7 [97]. …”

Extracellular ATP Selectively Upregulates Ecto-Nucleoside Triphosphate Diphosphohydrolase 2 and Ecto-5′-Nucleotidase by Rat Cortical Astrocytes In Vitro

“…It has been shown in different models of brain injury that ATP, by acting at ligand-gated P2X and G protein-coupled P2Y receptors (Abbracchio et al 2006), regulates several key aspects of the reactive astrocytic phenotype, including morphological remodeling, chemotaxis, and release of proinflammatory cytokines (Ciccarelli et al 1994;Neary et al 1994Neary et al , 1999Franke et al 2012;Minkiewicz et al 2013). Specifically, by acting at P2X7 receptor (Di Virgilio, 2007), ATP stimulates assembly of NOD-like receptor protein (Chakraborty et al 2010;Minkiewicz et al 2013) and activates caspase-1 which results in processing and secretion of IL-1β (Bours et al 2011). This cytokine appears to be essential for astrocyte activation and proliferation (Herx and Yong 2001;Dunn et al 2002;John et al 2004) as well as production and release of other proinflammatory cytokines (Liu et al 2000;Cahill and Rogers 2008), including tumor necrosis factor alpha (TNF-α) (Kucher and Neary, 2005;Zou et al 2012).…”

P2X7 receptor activation induces inflammatory responses in salivary gland epithelium

“…Accumulating evidence indicates that extracellular ATP (eATP) can act as a host-derived danger signal or damageassociated molecular pattern (19,74,92) that is capable of initiating inflammatory responses in a variety of cell and tissue types (8,25,46,74,83,84,107). Under physiological conditions, the concentration of eATP is tightly regulated, but under pathological conditions (i.e., stress, trauma, or inflammation) high levels of ATP are released into the extracellular milieu.…”