Goldstein Evan Z, Church Jamie S, Pukos Nicole, Gottipati Manoj K, Popovich Phillip G, McTigue Dana M
Neuroscience Graduate Program, The Ohio State University, Columbus, OH 43210, USA; Center for Brain and Spinal Cord Repair, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA.
Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA; Center for Brain and Spinal Cord Repair, Wexner Medical Center, The Ohio State University, Columbus, OH 43210, USA; Department of Biomedical Engineering, Center for Biotechnology and Interdisciplinary Sciences, Rensselaer Polytechnic Institute, Troy, NY 12180, USA.
Exp Neurol. 2017 Dec;298(Pt A):42-56. doi: 10.1016/j.expneurol.2017.08.015. Epub 2017 Aug 26.
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/macrophages 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.
铁对于基本的细胞功能至关重要，但过量时具有高度毒性。因此，外周的游离铁和铁储存通过精细的调节机制进行控制。相比之下，中枢神经系统（CNS）中的铁调节尚不明确。鉴于创伤、出血性中风和神经退行性变后会出现铁过量，了解正常的铁调节并促进中枢神经系统病理状态下的铁摄取至关重要。在外周，Toll样受体4（TLR4）激活可促进巨噬细胞对铁的螯合。值得注意的是，中枢神经系统病理状态下富含铁的部位通常含有TLR4激动剂，这可能促进铁的摄取。事实上，我们最近的研究表明，TLR4缺陷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来探究中枢神经系统中TLR4激活是否会刺激铁摄取并促进对铁诱导毒性的神经保护作用。为此，我们测量了小胶质细胞/巨噬细胞螯合外源性铁并在有无脊髓内TLR4激活伴随的情况下预防病理变化的能力。结果表明，与外周情况类似，通过局部注射脂多糖激活脊髓内TLR4可增加编码铁摄取和储存蛋白的mRNA表达，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丢失。此外，如果在TLR4激活的同时存在铁，祖细胞对少突胶质细胞的替代——这是对体内巨噬细胞TLR4激活的一种通常很强的反应——会显著减少。因此，虽然TLR4信号传导促进中枢神经系统铁摄取，但未来的工作需要确定在不阻断先天免疫受体信号传导的修复作用的情况下增强铁清除的方法。
