CNS-Derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells
CNS-Derived interleukin-4 is essential for the regulation of autoimmune inflammation and induces a state of alternative activation in microglial cells
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DOI：
10.1523/jneurosci.1922-07.2007
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发表时间：
2007-10-03
影响因子：
5.3
通讯作者：
Dittel, Bonnie N.
中科院分区：
文献类型：
--
作者：
Ponomarev, Eugene D.;Maresz, Katarzyna;Dittel, Bonnie N.
中枢神经系统炎症的调节对于防止神经退行性疾病(如多发性硬化症(MS))中可能发生的不可逆转的细胞损伤至关重要。我们利用实验性自身免疫性脑脊髓炎(EAE)的MS动物模型，研究了IL-4在调节中枢神经系统炎症中的作用。我们发现，中枢神经系统来源的IL-4是一个关键的调节因子，因为中枢神经系统IL-4产生不足的小鼠，与浸润性炎症细胞绝对数显著增加相关，加重了EAE。我们还发现，静息和激活状态下的中枢神经系统驻留的小胶质细胞都以IL-4依赖的方式产生YM1蛋白，该蛋白是交替激活的巨噬细胞(AAM Phi S)的标志。这种Aam Phi表型延伸到激活的小胶质细胞缺乏一氧化氮(NO)的产生，这是经典激活的巨噬细胞的标志。我们还发现，IL-4可诱导外周巨噬细胞表达YM1，而YM1也可产生NO。因此，迁移到中枢神经系统的巨噬细胞表现出双重表型。这些数据表明，中枢神经系统中IL-4的产生对于通过诱导小胶质细胞Aam Phi表型来控制自身免疫性炎症是必不可少的。经过交替激活的巨噬细胞已被证明在组织修复中很重要；因此，我们的结果表明，小胶质细胞在调节中枢神经系统炎症中发挥了新的作用。
Regulation of inflammation in the CNS is essential to prevent irreversible cellular damage that can occur in neurodegenerative diseases such as multiple sclerosis ( MS). We investigated the role of interleukin-4 ( IL-4) in regulating CNS inflammation using the animal model of MS, experimental autoimmune encephalomyelitis ( EAE). We found that CNS-derived IL-4 was a critical regulator because mice with a deficiency in IL-4 production in the CNS, but not the periphery, had exacerbated EAE associated with a significant increase in the absolute number of infiltrating inflammatory cells. We also found that CNS-resident microglial cells in both the resting and activated state produced the protein Ym1, which is a marker of alternatively activated macrophages ( aaM Phi s), in an IL-4-dependent manner. This aaM Phi phenotype extended to the lack of nitric oxide ( NO) production by activated microglial cells, which is a marker of classically activated macrophages. We also show that IL-4 induced the expression of Ym1 in peripheral infiltrating macrophages, which also produce NO. Thus, macrophages that migrate into the CNS exhibit a dual phenotype. These data indicate that IL-4 production in the CNS is essential for controlling autoimmune inflammation by inducing a microglial cell aaM Phi phenotype. Macrophages that have undergone alternative activation have been shown to be important in tissue repair; thus, our results suggest a new role for microglial cells in the regulation of inflammation in the CNS.