CD73-deficient mice display enhanced leukocyte extravasation at s

CD73-deficient mice display enhanced leukocyte extravasation at sites of inflammation in several ischemia-reperfusion models, and also the vascular permeability is increased in the absence of CD73 27. It has been firmly established that these effects are largely mediated by diminished adenosine production in these mice. However, the other enzymes involved in the inactivation and/or transphosphorylation of ATPADPAMP, and further degradation of Ferrostatin-1 cost AMP into adenosine and inosine have not been previously studied in the CD73-deficient mice. Here, we confirmed that CD73 was expressed both in a subpopulation of CD4+ and CD8+ T lymphocytes. T cells had significantly increased ATPase and ADPase

activities in the CD73-deficient mice. This suggests that the extracellular levels of proinflammatory ATP and procoagulant ADP molecules are lower in these mice. However, since extracellular AMP hydrolysis is also largely blocked in the absence of CD73, the concentration of extracellular adenosine, which is an anti-inflammatory molecule, is actually also decreased in the absence of CD73. Thus, the net effect of CD73 deficiency may be

to tilt the balance of purinergic signaling towards a state in Selleckchem Fulvestrant which AMP accumulates in the body. The tumor microenvironment is capable of diverting the inflammatory reaction in a way that paradoxically enhances tumor growth. Intratumoral infiltration of Tregs and intratumoral differentiation of type 1 macrophages into type 2 macrophages are two key events in this immune evasion process 23, 30–33. Our findings indicate that Histone demethylase the altered purinergic balance in the absence of CD73 inhibits this detrimental process, inasmuch the

tumors in CD73-deficient mice had specific decrease in the numbers of intratumoral Tregs and MR+ macrophages when compared with the WT mice. Interestingly, type 2 macrophages also show altered expression of purinergic receptors, which may link the CD73 and altered NTPDase activities to the observed phenotype 34. Moreover, tumor-infiltrating leukocytes in CD73-deficient mice showed increased IFN-γ synthesis. Since the transcription factor T-bet was actually down-regulated in tumor-infiltrating leukocytes in CD73-deficient mice, we speculate that IFN-γ is mainly produced by CD8+ cells, which in contrast to CD4+ and NK cells do not require T-bet for IFN-γ production 35. IFN-γ inhibits tumor formation and drives macrophage polarization into classically activated type 1, which show multiple anti-tumoral properties 30, 36. Notably, increased IFN-γ synthesis has also been recently reported in CD73-deficient mice during allograft rejection and in gastritis 37, 38. Interestingly, adenosine prevents IFN-γ-induced STAT phosphorylation and macrophage activation 39, and ATP has been reported to impair IFN-γ secretion in blood cells 35.

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