CD73 is required for efficient entry of lymphocytes into the central nervous system during experimental autoimmune encephalomyelitis

Abstract

CD73 is a cell surface enzyme of the purine catabolic pathway that catalyzes the breakdown of AMP to adenosine. Because of the strong immunosuppressive and antiinflammatory properties of adenosine, we predicted that cd73 ؊/؊ mice would develop severe experimental autoimmune encephalomyelitis (EAE), an animal model for the central nervous system (CNS) inflammatory disease, multiple sclerosis. Surprisingly, cd73 ؊/؊ mice were resistant to EAE. However, CD4 T cells from cd73 ؊/؊ mice secreted more proinflammatory cytokines than wild-type (WT) mice and were able to induce EAE when transferred into naïve cd73 ؉/؉ T cell-deficient recipients. Therefore, the protection from EAE observed in cd73 ؊/؊ mice was not caused by a deficiency in T cell responsiveness. Immunohistochemistry showed that cd73 ؊/؊ mice had fewer infiltrating lymphocytes in their CNS compared with WT mice. Importantly, susceptibility to EAE could be induced in cd73 ؊/؊ mice after the transfer of WT CD73 ؉ CD4 ؉ T cells, suggesting that CD73 must be expressed either on T cells or in the CNS for disease induction. In the search for the source of CD73 in the CNS that might facilitate lymphocyte migration, immunohistochemistry revealed a lack of CD73 expression on brain endothelial cells and high expression in the choroid plexus epithelium which regulates lymphocyte immunosurveillance between the blood and cerebrospinal fluid. Because blockade of adenosine receptor signaling with the A 2a adenosine receptor-specific antagonist SCH58261 protected WT mice from EAE induction, we conclude that CD73 expression and adenosine receptor signaling are required for the efficient entry of lymphocytes into the CNS during EAE development.adenosine ͉ multiple sclerosis ͉ inflammation ͉ choroid plexus

Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation

“…A 1 AR-KO mice developed a severe form of EAE with extensive damage in CNS, and activation of A 1 AR with agonist adenosine amine congener attenuated demyelination in EAE mice (6). Recently, mice with a genetic deficiency of CD73, an enzyme critical for the generation of extracellular adenosine, were unexpectedly found to be highly resistant to EAE (9). The authors also found A 2A AR antagonist SCH58261 protected mice from CNS injury in EAE.…”

“…It seems adenosine might act mainly through A 1 AR and A 2A AR to suppress inflammation. However, a recent study unexpectedly discovered that mice with a genetic deficiency in CD73, a nucleotidase critical for the generation of extracellular adenosine, are highly resistant to myelin oligodendrocyte glycoprotein (MOG)-induced brain and spinal cord injury (9), indicating a proinflammatory function of adenosine.…”

Extracellular adenosine triphosphate and adenosine in cancer

“…In contrast to its role in lymph nodes, CD73 promotes T-cell extravasation in peripheral tissue. Accordingly, decreased extravasation of pathogenic T cells was recently suggested as the cause of resistance of CD73-deficient mice to experimental autoimmune encephalomyelitis (Mills et al, 2008). Through the production of adenosine and the activation of adenosine receptors on endothelial cells, it was suggested that CD73 triggers adhesion molecules, such as intercellular adhesion molecule 1 on endothelial cells.…”

Functions of lipid raft membrane microdomains at the blood–brain barrier

“…Accordingly, knockdown of lipid raft-associated protein, caveolin-1, in ECs was shown to inhibit transendothelial leukocyte migration [93]. Recent studies using peripheralderived endothelium and epithelial cultures have identified novel molecules that coordinate leukocyte transmigration, including JAMs, CD44, CD47, CD73 [94], CD90 [95], CD137 [96], CD81 [97], CD99 [98], CD99L, and CD166/ ALCAM [99]. Most of these adhesion molecules are enriched in lipid rafts derived from primary cultures of human BECs [99].…”