P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis.
P2x7 deficiency suppresses development of experimental autoimmune encephalomyelitis.
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DOI：
10.1186/1742-2094-5-33
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发表时间：
2008-08-08
影响因子：
9.3
通讯作者：
Feinstein DL
中科院分区：
文献类型：
--
作者：
Sharp AJ;Polak PE;Simonini V;Lin SX;Richardson JC;Bongarzone ER;Feinstein DL
嘌呤能受体P2 x7在髓样细胞以及CNS神经胶质细胞上表达，并且P2 x7活化已显示增加神经胶质细胞和T细胞活化。这些特性表明它在包括多发性硬化症在内的自身免疫性疾病的发展中发挥着作用。在野生型C57 BL 6小鼠和与C57 BL 6小鼠回交的P2 x7缺陷型小鼠（“P2 x7小鼠”）中诱导使用髓鞘少突胶质细胞糖蛋白（MOG）肽残基35-55的MS、实验性自身免疫性脑脊髓炎（EAE）的动物模型。通过临床体征的出现、免疫细胞化学染色以评估脑炎症和神经元损伤以及通过测量T细胞细胞因子产生来监测疾病进展。与野生型小鼠相比，P2 x7小鼠中EAE疾病的发生率降低了4倍;然而，患病的P2 x7小鼠具有与野生型小鼠相似的发病天数和临床评分。与野生型细胞相比，从P2 x7缺失小鼠分离的脾T细胞产生更大的IFNγ和IL-17（3至12倍的水平），然而，选择性P2 x7激动剂不增加来自P2 x7衍生细胞的细胞因子产生，因为来自野生型细胞的细胞因子产生。虽然在P2 x7和野生型小鼠的脑中均检测到浸润细胞，但与野生型小鼠相比，星形胶质细胞活化和轴突损伤减少，并且星形胶质细胞活化的分布在两种品系中明显不同。相比之下，小胶质细胞的激活是相似的两个菌株。P2 x7缺陷导致代偿性变化，导致T细胞细胞因子产生增加，并且在无临床体征的P2 x7缺失小鼠的脑中检测到活化的T细胞。然而，大大降低的发病率表明，在这些小鼠中不存在起始事件，并指出星形胶质细胞P2 x7在EAE疾病发展中的作用。
The purinergic receptor P2x7 is expressed on myeloid cells as well as on CNS glial cells, and P2x7 activation has been shown to increase both glial and T-cell activation. These properties suggest a role in the development of autoimmune disease including multiple sclerosis. The animal model of MS, experimental autoimmune encephalomyelitis (EAE) using myelin oligodendrocyte glycoprotein (MOG) peptide residues 35–55 was induced in wildtype C57BL6 mice and in P2x7 deficient mice ('P2x7 mice') that were backcrossed to C57BL6 mice. Disease progression was monitored by appearance of clinical signs, immunocytochemical staining to assess brain inflammation and neuronal damage, and by measurement of Tcell cytokine production. The incidence of EAE disease in P2x7 mice was reduced 4-fold compared to the wildtype mice; however the P2x7 mice that became ill had similar days of onset and clinical scores as the wildtype mice. Splenic T-cells isolated from P2x7 null mice produced greater IFNγ and IL-17 (from 3 to 12 fold greater levels) than wildtype cells, however cytokine production from P2x7 derived cells was not increased by a selective P2x7 agonist as was cytokine production from wildtype cells. Although infiltrating cells were detected in brains of both the P2x7 and wildtype mice, astroglial activation and axonal damage was reduced versus wildtype mice, and the distribution of astroglial activation was markedly distinct in the two strains. In contrast, microglial activation was similar in the two strains. P2x7 deficiency resulted in compensatory changes leading to increased T-cell cytokine production, and activated T-cells were detected in the brains of P2x7 null mice with no clinical signs. However, the greatly reduced incidence of disease suggests that an initiating event is absent in these mice, and points to a role for astroglial P2x7 in development of EAE disease.
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