A2A Adenosine Receptor Signaling in Lymphocytes and the Central Nervous System Regulates Inflammation during Experimental Autoimmune Encephalomyelitis

Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
The Journal of Immunology (Impact Factor: 4.92). 04/2012; 188(11):5713-22. DOI: 10.4049/jimmunol.1200545
Source: PubMed


Extracellular adenosine has an important role in regulating the severity of inflammation during an immune response. Although there are four adenosine receptor (AR) subtypes, the A2AAR is both highly expressed on lymphocytes and known as a prime mediator of adenosine's anti-inflammatory effects. To define the importance of A2AAR signaling during neuroinflammatory disease progression, we used the experimental autoimmune encephalomyelitis (EAE) animal model for multiple sclerosis. In EAE induction experiments, A2AAR antagonist treatment protected mice from disease development and its associated CNS lymphocyte infiltration. However, A2AAR(-/-) mice developed a more severe acute EAE phenotype characterized by more proinflammatory lymphocytes and activated microglia/macrophages. Interestingly, very high levels of A2AAR were expressed on the choroid plexus, a well-established CNS lymphocyte entry point. To determine the contribution of A2AAR signaling in lymphocytes and the CNS during EAE, we used bone marrow chimeric mice. Remarkably, A2AAR(-/-) donor hematopoietic cells potentiated severe EAE, whereas lack of A2AAR expression on nonhematopoietic cells protected against disease development. Although no defect in the suppressive ability of A2AAR(-/-) regulatory T cells was observed, A2AAR(-/-) lymphocytes were shown to proliferate more and produced more IFN-γ following stimulation. Despite this more proinflammatory phenotype, A2AAR antagonist treatment still protected against EAE when A2AAR(-/-) lymphocytes were adoptively transferred to T cell-deficient A2AAR(+/+) mice. These results indicate that A2AAR expression on nonimmune cells (likely in the CNS) is required for efficient EAE development, while A2AAR lymphocyte expression is essential for limiting the severity of the inflammatory response.

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    • "In the A 2A RÀ/À mice, the acute presentation of EAE was less severe than WT controls. However, after 10 d the disease presentation was comparable (Mills et al., 2012). The same reduction in macrophage activation markers is seen in the spinal cord of EAE rats subsequent to IL-10 gene therapy administered intrathecally in EAE rats (Sloane et al., 2009). "
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    ABSTRACT: A single intrathecal dose of adenosine 2A receptor (A2AR) agonist was previously reported to produce a multi-week reversal of allodynia in two different models of neuropathic pain in addition to downregulating glial activation markers in the spinal cord. We aimed to determine whether a single intrathecal administration of an A2AR agonist was able to attenuate motor symptoms induced by experimental autoimmune encephalopathy. Two A2AR agonists (CGS21680 and ATL313) significantly attenuated progression of motor symptoms following a single intrathecal administration at the onset of motor symptoms. OX-42, a marker of microglial activation, was significantly attenuated in the lumbar spinal cord following A2AR administration compared to vehicle. Therefore, A2AR agonists attenuate motor symptoms of EAE by acting on A2AR in the spinal cord. Copyright © 2015. Published by Elsevier Inc.
    Brain Behavior and Immunity 01/2015; 46. DOI:10.1016/j.bbi.2015.01.014 · 5.89 Impact Factor
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    • "Adenosine resistance in supTh17 cells is likely to be conferred by low levels of A2A adenosine receptor and by higher levels of adenosine catalysis. The A2A adenosine receptor is primarily known to mediate anti-inflammatory effects: lymphocytes from A2A receptor (−/−) mice show higher rates of cell proliferation and produce high IFNγ levels upon stimulation [50]. A2A receptor stimulation has established inhibitory effects on Th1 and Th17 effector cell generation and, in contrast, favors generation of FOXP3+ and LAG-3+ regulatory T-cells [51]. "
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    ABSTRACT: Induced regulatory T-cells (iT-reg) and T helper type 17 (Th17) in the mouse share common CD4 progenitor cells and exhibit overlapping phenotypic and functional features. Here, we show that human Th17 cells endowed with suppressor activity (supTh17) can be derived following exposure of iT-reg populations to Th17 polarizing conditions. In contrast to "pathogenic" Th17, supTh17 display immune suppressive function and express high levels of CD39, an ectonucleotidase that catalyzes the conversion of pro-inflammatory extracellular nucleotides ultimately generating nucleosides. Accordingly, supTh17 exhibit nucleoside triphosphate diphosphohydrolase activity, as demonstrated by the efficient generation of extracellular AMP, adenosine and other purine derivatives. In addition supTh17 cells are resistant to the effects of adenosine as result of the low expression of the A2A receptor and accelerated adenosine catalysis by adenosine deaminase (ADA). These supTh17 can be detected in the blood and in the lamina propria of healthy subjects. However, these supTh17 cells are diminished in patients with Crohn's disease. In summary, we describe a human Th17 subpopulation with suppressor activity, which expresses high levels of CD39 and consequently produces extracellular adenosine. As these uniquely suppressive CD39(+) Th17 cells are decreased in patients with inflammatory bowel disease, our findings might have implications for the development of novel anti-inflammatory therapeutic approaches in these and potentially other immune disorders.
    PLoS ONE 02/2014; 9(2):e87956. DOI:10.1371/journal.pone.0087956 · 3.23 Impact Factor
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    • "Adenosine is an endogenous purine nucleoside that modulates a wide range of physiologic functions (7). Most notable among its many roles is its importance in controlling inflammation (8, 9) and inhibiting seizures (10–16). Adenosine is formed by dephosphorylation of adenosine monophosphate by ecto- and endo-5′-nucleotidase; through hydrolysis of S-adenylhomocysteine, it is removed by adenosine deaminase and adenosine kinase (ADK) (17). "
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    ABSTRACT: Rasmussen encephalitis (RE) is a rare neurologic disorder of childhood characterized by unihemispheric inflammation, progressive neurologic deficits, and intractable focal epilepsy. The pathogenesis of RE is still enigmatic. Adenosine is a key endogenous signaling molecule with anticonvulsive and anti-inflammatory effects, and our previous work demonstrated that dysfunction of the adenosine kinase (ADK)-adenosine system and astrogliosis are the hallmarks of epilepsy. We hypothesized that the epileptogenic mechanisms underlying RE are related to changes in ADK expression and that those changes might be associated with the development of epilepsy in RE patients. Immunohistochemistry was used to examine the expression of ADK and glial fibrillary acidic protein in surgically resected human epileptic cortical specimens from RE patients (n = 12) and compared with control cortical tissues (n = 6). Adenosine kinase expression using Western blot and enzymatic activity for ADK were assessed in RE versus control samples. Focal astrogliosis and marked expression of ADK were observed in the lesions of RE. Significantly greater ADK expression in RE versus controls was demonstrated by Western blot, and greater enzymatic activity for ADK was demonstrated using an enzyme-coupled bioluminescent assay. These results suggest that upregulation of ADK is a common pathologic hallmark of RE and that ADK might be a target in the treatment of epilepsy associated with RE.
    Journal of Neuropathology and Experimental Neurology 10/2013; DOI:10.1097/01.jnen.0000435369.39388.5c · 3.80 Impact Factor
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