Department of Pediatrics, University of Mississippi Medical Center, 2500 North State Street, Jackson, MS 39216, USA.
Neuroscience. 2010 Mar 17;166(2):464-75. doi: 10.1016/j.neuroscience.2009.12.040. Epub 2009 Dec 24.
Damage to oligodendrocyte (OL) progenitor cells (OPCs) and hypomyelination are two hallmark features of periventricular leukomalacia (PVL), the most common form of brain damage in premature infants. Clinical and animal studies have linked the incidence of PVL to maternal infection/inflammation, and activated microglia have been proposed to play a central role. However, the precise mechanism of how activated microglia adversely affects the survival and development of OPCs is still not clear. Here we demonstrate that lipopolysaccharide (LPS)-activated microglia are deleterious to OPCs, that is, impeding OL lineage progression, reducing the production of myelin basic protein (MBP), and mediating OPC death. We further demonstrate that LPS-activated microglia mediate OPC death by two distinct mechanisms in a time-dependent manner. The early phase of cell damage occurs within 24 h after LPS treatment, which is mediated by nitric oxide (NO)-dependent oxidative damage and is prevented by N(G)-nitro-l-arginine methyl ester (l-NAME), a general inhibitor of nitric oxide synthase. The delayed cell death is evident at 48 h after LPS treatment, is mediated by cytokines, and is prevented by blocking the activity of tumor necrosis factor-alpha (TNF-alpha) and pro-nerve growth factor (proNGF), but not by l-NAME. Furthermore, microglia-derived insulin-like growth factor-1 (IGF-1) and ciliary neurotrophic factor (CNTF) were significantly suppressed by LPS, and exogenous IGF-1 and CNTF synergistically protected OLs from death induced by LPS-treated microglia conditioned medium, indicating that a deficiency in trophic support may also be involved in OL death. Our finding that LPS-activated microglia not only induce two waves of cell death but also greatly impair OL development may shed some light on the mechanisms underlying selective white matter damage and hypomyelination in PVL.
少突胶质前体细胞（OPC）损伤和少突胶质发育不全是脑室周围白质软化症（PVL）的两个主要特征，PVL 是早产儿脑损伤最常见的形式。临床和动物研究将 PVL 的发病率与母体感染/炎症联系起来，并提出激活的小胶质细胞可能发挥核心作用。然而，激活的小胶质细胞如何对 OPC 的存活和发育产生不利影响的精确机制仍不清楚。在这里，我们证明脂多糖（LPS）激活的小胶质细胞对 OPC 具有危害性，即阻碍 OL 谱系进展、减少髓鞘碱性蛋白（MBP）的产生并介导 OPC 死亡。我们进一步证明，LPS 激活的小胶质细胞通过两种不同的机制在时间依赖性方式中介导 OPC 死亡。细胞损伤的早期阶段发生在 LPS 处理后 24 小时内，这是由一氧化氮（NO）依赖性氧化损伤介导的，可通过 N(G)-硝基-L-精氨酸甲酯（l-NAME）预防，l-NAME 是一氧化氮合酶的一般抑制剂。LPS 处理后 48 小时出现延迟性细胞死亡，由细胞因子介导，并可通过阻断肿瘤坏死因子-α（TNF-α）和神经营养因子（proNGF）的活性来预防，但不能通过 l-NAME 来预防。此外，LPS 显著抑制小胶质细胞衍生的胰岛素样生长因子-1（IGF-1）和睫状神经营养因子（CNTF），外源性 IGF-1 和 CNTF 协同保护 OL 免受 LPS 处理的小胶质细胞条件培养基诱导的死亡，表明营养支持不足也可能与 OL 死亡有关。我们的发现表明，LPS 激活的小胶质细胞不仅诱导了两波细胞死亡，而且还极大地损害了 OL 的发育，这可能为 PVL 中选择性白质损伤和少突胶质发育不全的机制提供一些启示。
