Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage
Intraspinal TLR4 activation promotes iron storage but does not protect neurons or oligodendrocytes from progressive iron-mediated damage
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DOI：
10.1016/j.expneurol.2017.08.015
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发表时间：
2017-12-01
影响因子：
5.3
通讯作者：
McTigue, Dana M.
中科院分区：
文献类型：
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作者：
Goldstein, Evan Z.;Church, Jamie S.;McTigue, Dana M.
铁是基本细胞功能所必需的，但过量是剧毒的。出于这个原因，游离铁和铁储存在外围由复杂的调节机制控制。与此相反，铁在中枢神经系统（CNS）的调节还没有得到很好的定义。鉴于创伤、出血性中风和神经变性后存在过量的铁，理解正常的铁调节和促进CNS病理中的铁摄取是至关重要的。在外周，Toll样受体4（TLR 4）活化促进巨噬细胞的铁螯合。值得注意的是，CNS病理学的富铁部位通常含有TLR 4激动剂，其可促进铁摄取。事实上，我们最近的工作表明，TLR 4缺乏的小鼠在急性脊髓损伤后铁储存受损。在这里，我们使用了一个简化模型，询问是否在中枢神经系统中的TLR 4激活刺激铁的吸收，并促进神经保护铁诱导的毒性。为此，我们测量了小胶质细胞/巨胶质细胞在伴有和不伴有椎管内TLR 4活化的情况下螯合外源性铁和预防病理的能力。结果表明，类似于外周，通过局灶性LPS注射激活脊髓内TLR 4增加了编码铁摄取和储存蛋白的mRNA，并促进铁螯合到表达铁蛋白的巨噬细胞中。然而，这并不能防止少突胶质细胞和神经元的损失。此外，少突胶质细胞被祖细胞取代-一种通常对体内巨噬细胞TLR 4活化的强烈反应-如果铁与TLR 4活化同时存在，则显著减少。因此，虽然TLR 4信号促进CNS铁摄取，但未来的工作需要确定在不阻断先天免疫受体信号的修复作用的情况下增强铁清除的方法。
Iron is essential for basic cellular functions but in excess is highly toxic. For this reason, free iron and iron storage are controlled in the periphery by elaborate regulatory mechanisms. In contrast, iron regulation in the central nervous system (CNS) is not well defined. Given that excess iron is present after trauma, hemorrhagic stroke and neurodegeneration, understanding normal iron regulation and promoting iron uptake in CNS pathology is crucial. Peripherally, toll-like receptor 4 (TLR4) activation promotes iron sequestration by macrophages. Notably, iron-rich sites of CNS pathology typically contain TLR4 agonists, which may promote iron uptake. Indeed, our recent work showed impaired iron storage after acute spinal cord injury in mice with TLR4 deficiency. Here we used a reductionist model to ask if TLR4 activation in the CNS stimulates iron uptake and promotes neuroprotection from iron-induced toxicity. For this, we measured the ability of microglia/macro-phages to sequester exogenous iron and prevent pathology with and without concomitant intraspinal TLR4 activation. Results show that, similar to the periphery, activating intraspinal TLR4 via focal LPS injection increased mRNA encoding iron uptake and storage proteins and promoted iron sequestration into ferritin-expressing macrophages. However, this did not prevent oligodendrocyte and neuron loss. Moreover, replacement of oligodendrocytes by progenitor cells - a normally robust response to in vivo macrophage TLR4 activation - was significantly reduced if iron was present concomitant with TLR4 activation. Thus, while TLR4 signaling promotes CNS iron uptake, future work needs to determine ways to enhance iron removal without blocking the reparative effects of innate immune receptor signaling.