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@ARTICLE{Ingwersen:807657,
      author       = {Ingwersen, J. and Wingerath, B. and Graf, J. and Lepka, K.
                      and Hofrichter, M. and Schröter, F. and Wedekind, F. and
                      Bauer, Andreas and Schrader, J. and Hartung, H.-P. and
                      Prozorovski, T. and Aktas, O.},
      title        = {{D}ual roles of the adenosine {A}2a receptor in autoimmune
                      neuroinflammation},
      journal      = {Journal of neuroinflammation},
      volume       = {13},
      number       = {1},
      issn         = {1742-2094},
      address      = {London},
      publisher    = {BioMed Central},
      reportid     = {FZJ-2016-02143},
      pages        = {48},
      year         = {2016},
      abstract     = {BackgroundConditions of inflammatory tissue distress are
                      associated with high extracellular levels of adenosine, due
                      to increased adenosine triphosphate (ATP) degradation upon
                      cellular stress or the release of extracellular ATP upon
                      cell death, which can be degraded to adenosine by
                      membrane-bound ecto-enzymes like CD39 and CD73. Adenosine is
                      recognised to mediate anti-inflammatory effects via the
                      adenosine A2a receptor (A2aR), as shown in experimental
                      models of arthritis. Here, using pharmacological
                      interventions and genetic inactivation, we investigated the
                      roles of A2aR in experimental autoimmune encephalomyelitis
                      (EAE), an animal model of multiple sclerosis (MS).MethodsWe
                      used two independent mouse EAE variants, i.e. active
                      immunization in C57BL/6 with myelin oligodendrocyte
                      glycoprotein (MOG)35-55 or transfer-EAE by proteolipid
                      protein (PLP)139-155-stimulated T lymphocytes and EAE in
                      mice treated with A2aR-agonist CGS21680 at different stages
                      of disease course and in mice lacking A2aR (A2aR−/−)
                      compared to direct wild-type littermates. In EAE, we
                      analysed myelin-specific proliferation and cytokine
                      synthesis ex vivo, as well as inflammation and demyelination
                      by immunohistochemistry. In vitro, we investigated the
                      effect of A2aR on migration of CD4+ T cells, macrophages and
                      microglia, as well as the impact of A2aR on phagocytosis of
                      macrophages and microglia. Statistical tests were
                      Mann-Whitney U and Student’s t test.ResultsWe found an
                      upregulation of A2aR in the central nervous system (CNS) in
                      EAE, predominantly detected on T cells and
                      macrophages/microglia within the inflamed tissue. Preventive
                      EAE treatment with A2aR-specific agonist inhibited
                      myelin-specific T cell proliferation ex vivo and ameliorated
                      disease, while application of the same agonist after disease
                      onset exacerbated non-remitting EAE progression and resulted
                      in more severe tissue destruction. Accordingly,
                      A2aR-deficient mice showed accelerated and exacerbated
                      disease manifestation with increased frequencies of IFN-γ-,
                      IL-17- and GM-CSF-producing CD4+ T helper cells and higher
                      numbers of inflammatory lesions in the early stage. However,
                      EAE quickly ameliorated and myelin debris accumulation was
                      lower in A2aR−/− mice. In vitro, activation of A2aR
                      inhibited phagocytosis of myelin by macrophages and primary
                      microglia as well as migration of CD4+ T cells, macrophages
                      and primary microglia.ConclusionsA2aR activation exerts a
                      complex pattern in chronic autoimmune neurodegeneration:
                      while providing anti-inflammatory effects on T cells and
                      thus protection at early stages, A2aR seems to play a
                      detrimental role during later stages of disease and may thus
                      contribute to sustained tissue damage within the inflamed
                      CNS.},
      cin          = {INM-2},
      ddc          = {610},
      cid          = {I:(DE-Juel1)INM-2-20090406},
      pnm          = {571 - Connectivity and Activity (POF3-571)},
      pid          = {G:(DE-HGF)POF3-571},
      typ          = {PUB:(DE-HGF)16},
      UT           = {WOS:000370952100001},
      pubmed       = {pmid:26920550},
      doi          = {10.1186/s12974-016-0512-z},
      url          = {https://juser.fz-juelich.de/record/807657},
}