Genetic inactivation of the adenosine A2A receptor exacerbates brain damage in mice with experimental autoimmune encephalomyelitis

Authors

  • Shu-Qin Yao,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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    • These authors contributed equally to the work.

  • Zheng-Zheng Li,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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    • These authors contributed equally to the work.

  • Qing-Yuan Huang,

    1. Department of Neurology, Boston University School of Medicine, Boston, USA
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  • Fang Li,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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  • Zhao-Wei Wang,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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  • Elisabete Augusto,

    1. Department of Neurology, Boston University School of Medicine, Boston, USA
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  • Jin-Cai He,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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  • Xiao-Tong Wang,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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  • Jiang-Fan Chen,

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
    2. Department of Neurology, Boston University School of Medicine, Boston, USA
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  • Rong-Yuan Zheng

    1. Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, P.R. China
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Address correspondence and reprint requests to Rong-Yuan Zheng, MD, Department of Neurology, the First Affiliated Hospital and Research Institute of Experimental Neurobiology, Wenzhou Medical College, Wenzhou, Zhejiang, 325000, P.R. China. E-mail: zhengry@yahoo.com.cn or Jiang-Fan Chen MD, PhD., Department of Neurology, Boston University School of Medicine, 715 Albany Street, C329, Boston, MA 02118. E-mail: chenjf@bu.edu

Abstract

Studies with multiple sclerosis patients and animal models of experimental autoimmune encephalomyelitis (EAE) implicate adenosine and adenosine receptors in modulation of neuroinflammation and brain injury. Although the involvement of the A1 receptor has been recently demonstrated, the role of the adenosine A2A receptor (A2AR) in development of EAE pathology is largely unknown. Using mice with genetic inactivation of the A2A receptor, we provide direct evidence that loss of the A2AR exacerbates EAE pathology in mice. Compared with wild-type mice, A2AR knockout mice injected with myelin oligodendroglia glycoprotein peptide had a higher incidence of EAE and exhibited higher neurological deficit scores and greater decrease in body weight. A2AR knockout mice displayed increased inflammatory cell infiltration and enhanced microglial cell activation in cortex, brainstem, and spinal cord. In addition, demyelination and axonal damage in brainstem were exacerbated, levels of Th1 cytokines increased, and Th2 cytokines decreased. Collectively, these findings suggest that extracellular adenosine acting at A2ARs triggers an important neuroprotective mechanism. Thus, the A2A receptor is a potential target for therapeutic approaches to multiple sclerosis.

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