Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions.
Aberrant production of tenascin-C in globoid cell leukodystrophy alters psychosine-induced microglial functions.
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DOI：
10.1097/nen.0000000000000117
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发表时间：
2014-10
影响因子：
3.2
通讯作者：
Crocker SJ
中科院分区：
文献类型：
--
作者：
Claycomb KI;Winokur PN;Johnson KM;Nicaise AM;Giampetruzzi AW;Sacino AV;Snyder EY;Barbarese E;Bongarzone ER;Crocker SJ
球样细胞脑白质营养不良（GLD），或克拉伯病，是一种罕见的，往往是致命的脱髓鞘疾病引起的突变，在半乳糖苷酶（galc）基因，导致积累的半乳糖鞘氨醇（'精神病'）。我们最近报道，细胞外基质（ECM）蛋白酶，基质金属蛋白酶（MMP）-3，在GLD升高，它调节精神分裂素诱导的小胶质细胞活化。在这里，我们研究了中枢神经系统ECM成分表达在人类GLD患者和抽搐的GLD小鼠模型，使用免疫组织化学。使用ECM蛋白作为底物评价ECM蛋白对原代小鼠小胶质细胞对精神病碱反应的影响，并通过定量实时聚合酶链反应（qRT-PCR）、免疫细胞化学和ELISA进行分析。对共培养的少突胶质细胞进行小胶质细胞毒性的功能分析，并通过乳糖脱氢酶测定测量细胞死亡。生腱蛋白-C（TnC）在人GLD和抽搐小鼠中相对于对照以更高水平表达。小胶质细胞对精神肽的反应被TnC增强，如通过增加“球状体样”细胞形成、MMP-3 mRNA表达和对培养物中少突胶质细胞的更高毒性所确定的。这些发现与TnC生长的小胶质细胞中向M1小胶质细胞表型的转变一致。因此，在GLD中升高的TnC表达改变了小胶质细胞对精神病碱的反应。这些数据提供了一个新的视角，并加强了对小胶质细胞在GLD发病机制中的作用的理解。
Globoid cell leukodystrophy (GLD), or Krabbe disease, is a rare and often fatal demyelinating disease caused by mutations in the galactocerebrosidase (galc) gene that result in accumulation of galactosylsphingosine (‘psychosine’). We recently reported that the extracellular matrix (ECM) protease, matrix metalloproteinase (MMP)-3, is elevated in GLD and that it regulates psychosine-induced microglial activation. Here, we examined central nervous system ECM component expression in human GLD patients and in the twitcher mouse model of GLD using immunohistochemistry. The influence of ECM proteins on primary murine microglial responses to psychosine was evaluated using ECM proteins as substrates and analyzed by quantitative real-time polymerase chain reaction (qRT-PCR), immunocytochemistry, and ELISA. Functional analysis of microglial cytotoxicity was performed on oligodendrocytes in co-culture and cell death was measured by lactose dehydrogenase assay. Tenascin-C (TnC) was expressed at higher levels in human GLD and in twitcher mice vs. controls. Microglial responses to psychosine were enhanced by TnC, as determined by an increase in ‘globoid-like’ cell formation, MMP-3 mRNA expression and higher toxicity toward oligodendrocytes in culture. These findings were consistent with a shift toward the M1 microglial phenotype in TnC grown microglia. Thus, elevated TnC expression in GLD modified microglial responses to psychosine. These data offer a novel perspective and enhance understanding of the microglial contribution to GLD pathogenesis.