Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, 07985, Republic of Korea; Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07985, Republic of Korea.
Department of Pharmacology, College of Medicine, Ewha Womans University, Seoul, 07985, Republic of Korea.
Neuropharmacology. 2018 May 1;133:202-215. doi: 10.1016/j.neuropharm.2018.01.038. Epub 2018 Jan 31.
We previously reported that the bone morphogenetic protein (BMP) antagonist, noggin, improved the repair process with an increase in the reactive microglia/macrophage population in the ischemic brain. Since BMP plays a role in intracellular iron homeostasis via the hepcidin/ferroportin axis, and iron is required for myelination, this study was aimed to determine whether noggin affected iron status and remyelination in the brain following ischemic stroke. We further examined the effect of blocking the BMP/hepcidin pathway on reactive microglia (BV2) and myelination of oligodendroglial cells (MO3.13) to define the link between microglial iron status and myelin formation. Following the noggin infusion into the ischemic brain of mice, the induction of hepcidin and ferritin protein levels decreased, and the number of myelinated axons and myelin thickness increased at 8 weeks after ischemic stroke. Noggin repressed the increase in hepcidin and ferritin levels in BV2 exposed to lipopolysaccharide (LPS) and oxygen/glucose deprivation and reperfusion (OGD/R). When MO3.13 were exposed to the conditioned media from noggin-treated BV2 (noggin CM) during reperfusion, OGD/R-induced MO3.13 cell death was reduced. Under normal conditions, noggin CM induced myelin production with an increase in ferritin levels in MO3.13, which was reversed by the iron chelator, deferoxamine. These results indicated that noggin altered the iron status in reactive microglia from the iron-storing to the iron-releasing phenotype, which contributed to myelin synthesis by providing iron. We suggest that the BMP/hepcidin pathway can be a target for the regulation of the iron status in microglia to enhance remyelination in the ischemic brain.
我们之前报道称，骨形态发生蛋白（BMP）拮抗剂 Noggin 通过增加缺血性脑内反应性小胶质细胞/巨噬细胞的数量来改善修复过程。由于 BMP 通过铁调素/亚铁转运蛋白轴在细胞内铁稳态中发挥作用，而铁是髓鞘形成所必需的，因此本研究旨在确定 Noggin 是否会影响缺血性中风后大脑中的铁状态和髓鞘形成。我们进一步研究了阻断 BMP/铁调素通路对反应性小胶质细胞（BV2）和少突胶质细胞（MO3.13）髓鞘形成的影响，以确定小胶质细胞铁状态与髓鞘形成之间的联系。在 Noggin 输注到缺血性小鼠脑内后，铁调素和铁蛋白蛋白水平的诱导降低，并且在缺血性中风后 8 周时，髓鞘化轴突的数量和髓鞘厚度增加。Noggin 抑制 LPS 暴露的 BV2 和氧/葡萄糖剥夺再灌注（OGD/R）中 hepcidin 和 ferritin 水平的增加。当 MO3.13 在再灌注期间暴露于 Noggin 处理的 BV2 的条件培养基（noggin CM）时，OGD/R 诱导的 MO3.13 细胞死亡减少。在正常情况下，noggin CM 诱导 MO3.13 产生髓鞘，同时 ferritin 水平升高，这种作用可被铁螯合剂去铁胺逆转。这些结果表明，Noggin 将反应性小胶质细胞中的铁状态从储存铁表型转变为释放铁表型，从而通过提供铁来促进髓鞘合成。我们认为，BMP/铁调素通路可以作为调节小胶质细胞中铁状态以增强缺血性脑内髓鞘形成的靶点。
