Deletion of CD38 Suppresses Glial Activation and Neuroinflammation in a Mouse Model of Demyelination
Deletion of CD38 Suppresses Glial Activation and Neuroinflammation in a Mouse Model of Demyelination
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DOI：
10.3389/fncel.2019.00258
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发表时间：
2019-06-06
影响因子：
5.3
通讯作者：
Hori, Osamu
中科院分区：
文献类型：
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作者：
Roboon, Jureepon;Hattori, Tsuyoshi;Hori, Osamu
CD38 是一种催化从烟酰胺腺嘌呤二核苷酸 (NAD+) 合成环状腺苷二磷酸核糖的酶。我们最近报道，这种分子调节发育中大脑中星形胶质细胞和少突胶质细胞（OL）等神经胶质细胞的成熟和分化。为了分析其在脱髓鞘情况中的作用，我们采用铜宗 (CPZ) 诱导的小鼠脱髓鞘模型，其特点是少突胶质细胞特异性凋亡，随后是胶质细胞的强烈激活、脱髓鞘和 OL 的重新增殖。通过使用该模型，我们发现 CPZ 给药后星形胶质细胞和小胶质细胞中 CD38 均上调。使用野生型和 CD38 敲除 (KO) 小鼠以及使用培养的神经胶质细胞进行的实验表明，CD38 缺乏并不影响 OL 数量的最初减少，但它减弱了 CPZ 诱导的脱髓鞘和神经变性。重要的是，CD38 KO 小鼠中降解的髓磷脂的清除和少突胶质细胞的重新增殖也有所减少。进一步的实验表明，这些观察结果与神经胶质细胞活化和包括吞噬作用在内的炎症反应水平降低有关，很可能是通过 CD38 缺失条件下 NAD+ 水平的增强而实现的。我们的结果表明，神经胶质细胞中的 CD38 和 NAD+ 通过调节神经胶质活性和神经炎症，在脱髓鞘和随后的少突胶质细胞重塑中发挥着关键作用。
CD38 is an enzyme that catalyzes the synthesis of cyclic adenosine diphosphate-ribose from nicotinamide adenine dinucleotide (NAD+). We recently reported that this molecule regulates the maturation and differentiation of glial cells such as astrocytes and oligodendrocytes (OLs) in the developing brain. To analyze its role in the demyelinating situation, we employed cuprizone (CPZ)-induced demyelination model in mice, which is characterized by oligodendrocyte-specific apoptosis, followed by the strong glial activation, demyelination, and repopulation of OLs. By using this model, we found that CD38 was upregulated in both astrocytes and microglia after CPZ administration. Experiments using wild-type and CD38 knockout (KO) mice, together with those using cultured glial cells, revealed that CD38 deficiency did not affect the initial decrease of the number of OLs, while it attenuated CPZ-induced demyelination, and neurodegeneration. Importantly, the clearance of the degraded myelin and oligodendrocyte repopulation were also reduced in CD38 KO mice. Further experiments revealed that these observations were associated with reduced levels of glial activation and inflammatory responses including phagocytosis, most likely through the enhanced level of NAD+ in CD38-deleted condition. Our results suggest that CD38 and NAD+ in the glial cells play a critical role in the demyelination and subsequent oligodendrocyte remodeling through the modulation of glial activity and neuroinflammation.