Cuprizone demyelination induces a unique inflammatory response in the subventricular zone.
Cuprizone demyelination induces a unique inflammatory response in the subventricular zone.
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DOI：
10.1186/s12974-016-0651-2
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发表时间：
2016-08-22
影响因子：
9.3
通讯作者：
Szele FG
中科院分区：
文献类型：
--
作者：
Hillis JM;Davies J;Mundim MV;Al-Dalahmah O;Szele FG
Cuprizone 会导致胼胝体 (CC) 脱髓鞘，并激活相邻室下区 (SVZ) 中的祖细胞，SVZ 是一个有助于髓鞘再生的干细胞生态位。健康的 SVZ 含有半激活的小胶质细胞，并持续表达促炎分子半乳糖凝集素 3 (Gal-3)，表明该生态位独特地调节炎症。我们使用免疫组织化学和体外神经球测定研究了 Gal-3 敲除小鼠 SVZ 和 CC 中铜宗的炎症反应。铜宗导致 CC 中髓磷脂碱性蛋白 (MBP) 免疫荧光丧失，表明脱髓鞘。 Cuprizone 增加了 CC 中 CD45+/Iba1+ 小胶质细胞的密度，并增加了 Gal-3 的表达。令人惊讶的是，使用铜宗后，SVZ 中 Gal-3+ 和 CD45+ 细胞的数量减少，表明其中的炎症选择性减少。炎症可以调节 SVZ 增殖，事实上，在铜宗处理后，两种基因型的 SVZ 中磷酸组蛋白 H3+ (PHi3+) 细胞的数量减少，但 CC 中的数量增加。铜宗治疗后 SVZ 中的 BrdU+ SVZ 细胞数量也减少，并且与 WT 相比，Gal-3−/− 小鼠在 3 周时这种效应显着更大，表明 Gal-3 通常会限制铜宗治疗后 SVZ 细胞的迁移。这项研究揭示了 SVZ 中独特调节的炎症反应，并表明 Gal-3 参与铜宗模型中的髓鞘再生。这与引起 SVZ 炎症的更严重的脱髓鞘模型形成对比，并表明脱髓鞘的程度影响 SVZ 神经源性反应。本文的在线版本 (doi:10.1186/s12974-016-0651-2) 包含补充材料，可供授权用户使用。
Cuprizone leads to demyelination of the corpus callosum (CC) and activates progenitor cells in the adjacent subventricular zone (SVZ), a stem cell niche which contributes to remyelination. The healthy SVZ contains semi-activated microglia and constitutively expresses the pro-inflammatory molecule galectin-3 (Gal-3) suggesting the niche uniquely regulates inflammation. We studied the inflammatory response to cuprizone in the SVZ and CC in Gal-3 knockout mice using immunohistochemistry and with the in vitro neurosphere assay. Cuprizone caused loss of myelin basic protein (MBP) immunofluorescence in the CC suggesting demyelination. Cuprizone increased the density of CD45+/Iba1+ microglial cells and also increased Gal-3 expression in the CC. Surprisingly, the number of Gal-3+ and CD45+ cells decreased in the SVZ after cuprizone, suggesting inflammation was selectively reduced therein. Inflammation can regulate SVZ proliferation and indeed the number of phosphohistone H3+ (PHi3+) cells decreased in the SVZ but increased in the CC in both genotypes after cuprizone treatment. BrdU+ SVZ cell numbers also decreased in the SVZ after cuprizone, and this effect was significantly greater at 3 weeks in Gal-3−/− mice compared to WT, suggesting Gal-3 normally limits SVZ cell emigration following cuprizone treatment. This study reveals a uniquely regulated inflammatory response in the SVZ and shows that Gal-3 participates in remyelination in the cuprizone model. This contrasts with more severe models of demyelination which induce SVZ inflammation and suggests the extent of demyelination affects the SVZ neurogenic response. The online version of this article (doi:10.1186/s12974-016-0651-2) contains supplementary material, which is available to authorized users.