Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation
Blocking A2B Adenosine Receptor Alleviates Pathogenesis of Experimental Autoimmune Encephalomyelitis via Inhibition of IL-6 Production and Th17 Differentiation
复制标题
阻断 A2B 腺苷受体通过抑制 IL-6 产生和 Th17 分化减轻实验性自身免疫性脑脊髓炎的发病机制
DOI：
10.4049/jimmunol.1103721
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发表时间：
2013-01-01
影响因子：
4.4
通讯作者：
Xie, Xin
中科院分区：
文献类型：
--
作者：
Wei, Wei;Du, Changsheng;Xie, Xin
腺苷是调节免疫应答的关键内源性信号分子。A（2B）腺苷受体（AR）是腺苷的相对低亲和力受体，并且A（2B）AR的激活被认为需要与缺血、炎症、创伤或其他类型的应激相关的病理水平的腺苷。A（2B）AR在多发性硬化（MS）发病机制中的作用尚不清楚。在本研究中，我们发现A（2B）AR在MS患者的外周血白细胞和实验性自身免疫性脑脊髓炎（EAE）小鼠的外周淋巴组织中均上调。A（2B）AR特异性拮抗剂CVT-6883和MRS-1754减轻了EAE的临床症状并保护CNS免受免疫损伤。A（2B）AR基因敲除小鼠也发生了不太严重的EAE。进一步的研究表明，阻断或缺失A（2B）AR通过阻断来自APC如树突状细胞的IL-6产生来抑制Th 17细胞分化。在树突状细胞中，A（2B）AR在EAE的发展过程中也上调。CVT-6883和A（2B）AR基因缺失显著降低腺苷介导的IL-6产生。磷脂酶C β蛋白激酶C和p38 MAPK通路参与了A（2B）AR介导的IL-6产生。我们的研究结果不仅揭示了A（2B）AR在EAE中的病理作用，而且提示该受体可能成为开发抗MS药物的新靶点。免疫学杂志，2013，190：138-146。
Adenosine is a key endogenous signaling molecule that regulates immune responses. A(2B) adenosine receptor (AR) is a relatively low-affinity receptor for adenosine, and the activation of A(2B)AR is believed to require pathological level of adenosine that is associated with ischemia, inflammation, trauma, or other types of stress. The role of A(2B)AR in the pathogenesis of multiple sclerosis (MS) is still unclear. In this study, we discovered that A(2B)AR was upregulated both in the peripheral blood leukocytes of MS patients and the peripheral lymphoid tissues of experimental autoimmune encephalomyelitis (EAE) mice. A(2B)AR-specific antagonists, CVT-6883 and MRS-1754, alleviated the clinical symptoms of EAE and protected the CNS from immune damage. A(2B)AR-knockout mice also developed less severe EAE. Further study indicated that blocking or deleting A(2B)AR inhibited Th17 cell differentiation by blocking IL-6 production from APCs such as dendritic cells. In dendritic cells, A(2B)AR was also upregulated during the development of EAE. CVT-6883 and genetic deletion of A(2B)AR significantly reduced adenosine-mediated IL-6 production. The phospholipase C beta-protein kinase C and p38 MAPK pathways were found to be involved in the A(2B)AR-mediated IL-6 production. Our findings not only revealed the pathological role of A(2B)AR in EAE, but also suggested that this receptor might be a new therapeutic target for the development of anti-MS drugs. The Journal of Immunology, 2013, 190: 138-146.