Blocking a2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation

Wei Wei, Changsheng Du, Jie Lv, Guixian Zhao, Zhenxin Li, Zhiying Wu, G. Haskó, Xin Xie

Research output: Contribution to journalArticle

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Abstract

Adenosine is a key endogenous signaling molecule that regulates immune responses. A2B adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A2BAR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A2BAR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A2BAR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A2BAR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A2BAR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A2BAR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A2BAR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A2BAR significantly reduced adenosine-mediated IL-6 production. The phospholipase Cβ-protein kinase C and p38 MAPK pathways were found to be involved in the A2BAR-mediated IL- 6 production. Our findings not only revealed the pathological role of A2BAR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs.

Original languageEnglish
Pages (from-to)138-146
Number of pages9
JournalJournal of Immunology
Volume190
Issue number1
DOIs
Publication statusPublished - Jan 1 2013

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Purinergic P1 Receptors
Autoimmune Experimental Encephalomyelitis
Interleukin-6
Adenosine
Multiple Sclerosis
Dendritic Cells
Adenosine A2B Receptors
Th17 Cells
Type C Phospholipases
Lymphoid Tissue
p38 Mitogen-Activated Protein Kinases
Knockout Mice
Protein Kinase C
Cell Differentiation
Leukocytes
Ischemia
Inflammation
Wounds and Injuries
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Blocking a2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation. / Wei, Wei; Du, Changsheng; Lv, Jie; Zhao, Guixian; Li, Zhenxin; Wu, Zhiying; Haskó, G.; Xie, Xin.

In: Journal of Immunology, Vol. 190, No. 1, 01.01.2013, p. 138-146.

Research output: Contribution to journalArticle

Wei, Wei ; Du, Changsheng ; Lv, Jie ; Zhao, Guixian ; Li, Zhenxin ; Wu, Zhiying ; Haskó, G. ; Xie, Xin. / Blocking a2B adenosine receptor alleviates pathogenesis of experimental autoimmune encephalomyelitis via inhibition of IL-6 production and Th17 differentiation. In: Journal of Immunology. 2013 ; Vol. 190, No. 1. pp. 138-146.
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