Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease.
Post-CNS-inflammation expression of CXCL12 promotes the endogenous myelin/neuronal repair capacity following spontaneous recovery from multiple sclerosis-like disease.
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DOI：
10.1186/s12974-015-0468-4
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发表时间：
2016-01-08
影响因子：
9.3
通讯作者：
Ben-Nun A
中科院分区：
文献类型：
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作者：
Zilkha-Falb R;Kaushansky N;Kawakami N;Ben-Nun A
脱髓鞘和轴突变性是多发性硬化症（MS）的标志，与C-X-C基序趋化因子12 （CXCL12）趋化因子促进的中枢神经系统（CNS）炎症有关。在MS和实验性自身免疫性脑脊髓炎（EAE）中，有害的CNS炎症与CNS中CXCL12表达上调有关。我们研究了CXCL12在临床EAE进展和自发恢复后的中枢神经系统中的表达动态，重点研究了CXCL12在自发恢复小鼠海马神经源性齿状回（DG）和胼胝体（CC）中的表达，及其在促进内源性髓鞘/神经元修复能力中的潜在作用。采用免疫荧光染色和共聚焦成像技术，对不同临床EAE期、自然恢复及体外分化成体神经干细胞培养小鼠的中枢神经系统组织切片进行分析，检测和计数神经元祖细胞（npc）和少突胶质前体细胞（OPCs），并检测CXCL12的表达。我们对CXCL12在EAE进展的中枢神经系统中的表达动态分析显示，CXCL12在DG和CC中的表达升高，即使中枢神经系统炎症消退，CXCL12在自发恢复后仍持续升高。相应地，与naïve小鼠（npc, p < 0.0001; OPCs, p < 0.00001）或活跃性疾病小鼠（OPCs, p < 0.0005）相比，eae恢复小鼠DG和CC中npc和OPCs的数量增加。值得注意的是，大约30%的npc和出乎意料的OPCs（约50%）表达CXCL12，并且在EAE恢复的小鼠中，它们在DG和CC中的数量分别高于naïve小鼠和持续临床EAE的小鼠（CXCL12+ npc, p < 0.005; CXCL12+ OPCs, p < 0.0005）。此外，相当比例（bbb20 %）的CXCL12+ npc和OPCs共同表达CXCL12受体CXCR4，它们的数量随着EAE的恢复而显著增加，不仅相对于naïve小鼠（p < 0.0002），而且相对于持续EAE的小鼠（p < 0.004）。这些数据将eae恢复小鼠DG和CC中CXCL12的表达与促进神经/少突胶质发生联系起来，产生CXCR4+ CXCL12+神经元和少突胶质细胞祖细胞，这些祖细胞具有内在的神经/少突胶质分化潜能。这些发现强调了CXCL12可能通过CXCL12/CXCR4自分泌信号通路，在ms样疾病中增强内源性髓磷脂/神经元修复能力的中枢神经系统炎症后作用。本文的在线版本（doi:10.1186/s12974-015-0468-4）包含补充材料，可供授权用户使用。
Demyelination and axonal degeneration, hallmarks of multiple sclerosis (MS), are associated with the central nervous system (CNS) inflammation facilitated by C-X-C motif chemokine 12 (CXCL12) chemokine. Both in MS and in experimental autoimmune encephalomyelitis (EAE), the deleterious CNS inflammation has been associated with upregulation of CXCL12 expression in the CNS. We investigated the expression dynamics of CXCL12 in the CNS with progression of clinical EAE and following spontaneous recovery, with a focus on CXCL12 expression in the hippocampal neurogenic dentate gyrus (DG) and in the corpus callosum (CC) of spontaneously recovered mice, and its potential role in promoting the endogenous myelin/neuronal repair capacity. CNS tissue sections from mice with different clinical EAE phases or following spontaneous recovery and in vitro differentiated adult neural stem cell cultures were analyzed by immunofluorescent staining and confocal imaging for detecting and enumerating neuronal progenitor cells (NPCs) and oligodendrocyte precursor cells (OPCs) and for expression of CXCL12. Our expression dynamics analysis of CXCL12 in the CNS with EAE progression revealed elevated CXCL12 expression in the DG and CC, which persistently increases following spontaneous recovery even though CNS inflammation has subsided. Correspondingly, the numbers of NPCs and OPCs in the DG and CC, respectively, of EAE-recovered mice increased compared to that of naïve mice (NPCs, p < 0.0001; OPCs, p < 0.00001) or mice with active disease (OPCs, p < 0.0005). Notably, about 30 % of the NPCs and unexpectedly also OPCs (~50 %) express CXCL12, and their numbers in DG and CC, respectively, are higher in EAE-recovered mice compared with naïve mice and also compared with mice with ongoing clinical EAE (CXCL12+ NPCs, p < 0.005; CXCL12+ OPCs, p < 0.0005). Moreover, a significant proportion (>20 %) of the CXCL12+ NPCs and OPCs co-express the CXCL12 receptor, CXCR4, and their numbers significantly increase with recovery from EAE not only relative to naïve mice (p < 0.0002) but also to mice with ongoing EAE (p < 0.004). These data link CXCL12 expression in the DG and CC of EAE-recovering mice to the promotion of neuro/oligodendrogenesis generating CXCR4+ CXCL12+ neuronal and oligodendrocyte progenitor cells endowed with intrinsic neuro/oligondendroglial differentiation potential. These findings highlight the post-CNS-inflammation role of CXCL12 in augmenting the endogenous myelin/neuronal repair capacity in MS-like disease, likely via CXCL12/CXCR4 autocrine signaling. The online version of this article (doi:10.1186/s12974-015-0468-4) contains supplementary material, which is available to authorized users.