Mice lacking CD39 show exacerbated inflammation, which is connected with increased trafficking of both monocytes and neutrophils. The enhanced motility is due to the increased levels of CD11b/CD18 expression that are regulated by CD39 acting via the P2X7 receptor 40, 41.

CD73 is the key enzyme controlling degradation of AMP to adenosine. CD73 is broadly expressed on blood vessel endothelium and afferent lymphatics, but is absent from efferent lymphatic vessels. Subsets of lymphocytes, selleck chemicals especially regulatory T cells, are also CD73 positive. Engagement of lymphocyte CD73 induces clustering of LFA-1, and thus facilitates lymphocyte adhesion to the endothelium. When leukocytes adhere to endothelial cells, the enzymatic activity of the endothelial CD73 is inhibited. This leads to a decrease in adenosine production and, at the same time, the pre-existing adenosine is degraded by adenosine deaminase, which is bound to CD26 on the lymphocyte surface. In the absence of adenosine, the endothelial barrier becomes leakier facilitating leukocyte transmigration from the blood into the tissue 42. On vascular endothelial cells, adenosine generated via CD73 also inhibits

the expression of E-selectin and VCAM-1, contributing to anti-adhesive effects. H 89 solubility dmso CD73 on the lymphatic endothelium does not seem to have such an elemental function in barrier maintenance as it does on blood vessels, possibly due to the discontinuous and loose nature of interendothelial junctions in the lymphatic endothelium. However, lymphocyte CD73 is intimately involved in lymphocyte migration via afferent lymphatics to the draining LNs 43. CD73 knockout mice have recapitulated the

importance of CD73; they have leaky vasculature in different inflammatory and hypoxic models 44–46 and, simultaneously, increased mafosfamide leukocyte trafficking to sites of inflammation is observed. Interestingly, the CD73 knockout mice have a diminished number of tumor-infiltrating regulatory T cells and/or type II macrophages, although the total number of tumor-infiltrating leukocytes is unchanged 47–49. This suggests that complex regulatory mechanisms are active in tumors and they, at least partially, differ from those functioning at sites of inflammation. Autotaxin is primarily an extracellular lysophospholipase D that mainly produces lysophosphatic acid (LPA) and, to a lesser extent, sphingosine 1 phosphate 3, 50 (Fig. 2); however, autotaxin may also convert ATP and its degradation products to ADP, AMP and adenosine via additional enzymatic activities 3. Autotaxin is secreted from and binds to endothelial cells in high endothelial venules, and then interacts with integrins, such as α4β1, on the extravasating lymphocytes to facilitate the transmigration process 51, 52. LPA has been connected to atherogenesis as it causes release of CXCL1 from endothelium that then elicits monocyte adhesion to the arterial vessel wall 53.