Abstract
Various pathological conditions are accompanied by ATP release from the intracellular to the extracellular compartment. Extracellular ATP (eATP) functions as a signaling molecule by activating purinergic P2 purine receptors. The key P2 receptor involved in inflammation was identified as P2X7R. Recent studies have shown that P2X7R signaling is required to trigger the Th1/Th17 immune response, and oxidized ATP (oxATP) effectively blocks P2X7R activation. In this study we investigated the effect of oxATP on mouse experimental autoimmune uveitis (EAU). Our results demonstrated that induced EAU in B6 mice was almost completely abolished by the administration of small doses of oxATP, and the Th17 response, but not the Th1 response, was significantly weakened in the treated mice. Mechanistic studies showed that the therapeutic effects involve the functional change of a number of immune cells, including dendritic cells (DCs), T cells, and regulatory T cells. OxATP not only directly inhibits the T cell response; it also suppresses T cell activation by altering the function of DCs and Foxp3+ T cell. Our results demonstrated that inhibition of P2X7R activation effectively exempts excessive autoimmune inflammation, which may indicate a possible therapeutic use in the treatment of autoimmune diseases.
Highlights
During the past two decades, increasing evidence has shown that tissue stress or damage is closely associated with increased release of ATP from the intracellular into the extracellular compartment; this increased ATP release, in turn, exerts a strong modulatory effect on immune responses and inflammation [1,2,3,4,5,6,7,8]
The results showed that mice that received oxidized ATP (oxATP) treatment had almost undetected experimental autoimmune uveitis (EAU), as shown by fundoscopic (Fig 1A and 1B) and pathologic examination, whereas in the untreated mice massive inflammatory cell infiltration was found in the posterior chamber, mainly in the vitreous and retinal layers with serous exudates and subretinal bleeding (Fig 1C)
Studies have shown that binding of Extracellular ATP (eATP) to P2 receptors modulated various inflammatory responses, including infections and tumors [1] and the inflammation induced during ischemia and reperfusion, as well as the inflammation that occurs in various disease states such as intestinal and lung diseases [49,50], type 1 diabetes, rheumatoid arthritis and multiple sclerosis [51] and graft-versus-host disease [28]
Summary
During the past two decades, increasing evidence has shown that tissue stress or damage is closely associated with increased release of ATP from the intracellular into the extracellular compartment; this increased ATP release, in turn, exerts a strong modulatory effect on immune responses and inflammation [1,2,3,4,5,6,7,8]. Many cell types are able to release ATP [3,5,9,10]. Receptors that bind ATP, designated as P2 receptors, are widely expressed on virtually all cell types, including immune cells [11,12,13,14,15]. Activation of P2 receptors by ATP effectively. Effect of Oxidized ATP on EAU modulates various immune responses. Studies revealed that modulations of the extracellular ATP/adenosine metabolism or manipulation of the binding of ATP metabolites to specific receptors could generate a strong effect on immune responses [6,16,18]. Among the receptors that bind ATP, P2X7R is most abundantly expressed on mouse CD4+ T cells [28,30]
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