Liu B, Wang K, Gao H M, Mandavilli B, Wang J Y, Hong J S
Neuropharmacology Section, Laboratory of Pharmacology and Chemistry, National Institute of Environmental Health Sciences/National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
J Neurochem. 2001 Apr;77(1):182-9. doi: 10.1046/j.1471-4159.2001.t01-1-00216.x.
Microglia, the resident immune cells in the brain, play a pivotal role in immune surveillance, host defense, and tissue repair in the CNS. In response to immunological challenges, microglia readily become activated as characterized by morphological changes, expression of surface antigens, and production of immune modulators that impact on neurons to induce neurodegeneration. However, little is known concerning the fate of activated microglia. In the present study, stimulation of cultured rat primary microglia with 1 ng/mL of the inflammagen lipopolysaccharide (LPS) resulted in a maximal activation as measured by the release of tumor necrosis factor alpha (TNF alpha). However, treatment with higher concentrations of LPS resulted in significantly lower quantities of detectable TNF alpha. Further analysis revealed that overactivation of microglia with higher concentrations of LPS (> 1 ng/mL) resulted in a time- and dose-dependent apoptotic death of microglia as defined by DNA strand breaks, surface expression of apoptosis-specific markers (phosphatidylserine), and activation of caspase-3. In contrast, astrocytes were insensitive to LPS-induced cytotoxicity. In light of the importance of microglia and the limited replenishment mechanism, depletion of microglia from the brain may severely hamper its capacity for combating inflammatory challenges and tissue repair. Furthermore, overactivation-induced apoptosis of microglia may be a fundamental self-regulatory mechanism devised to limit bystander killing of vulnerable neurons.
小胶质细胞是大脑中的常驻免疫细胞，在中枢神经系统的免疫监视、宿主防御和组织修复中发挥着关键作用。在应对免疫挑战时，小胶质细胞很容易被激活，其特征表现为形态变化、表面抗原表达以及产生影响神经元从而诱导神经退行性变的免疫调节剂。然而，关于激活的小胶质细胞的命运却知之甚少。在本研究中，用1 ng/mL炎症因子脂多糖（LPS）刺激培养的大鼠原代小胶质细胞，通过肿瘤坏死因子α（TNFα）的释放来衡量，可导致最大程度的激活。然而，用更高浓度的LPS处理导致可检测到的TNFα数量显著减少。进一步分析表明，用更高浓度的LPS（>1 ng/mL）过度激活小胶质细胞会导致小胶质细胞发生时间和剂量依赖性的凋亡死亡，这由DNA链断裂、凋亡特异性标志物（磷脂酰丝氨酸）的表面表达以及半胱天冬酶-3的激活所定义。相比之下，星形胶质细胞对LPS诱导的细胞毒性不敏感。鉴于小胶质细胞的重要性以及其有限的补充机制，大脑中小胶质细胞的耗竭可能会严重阻碍其对抗炎症挑战和组织修复的能力。此外，过度激活诱导的小胶质细胞凋亡可能是一种基本的自我调节机制，旨在限制对脆弱神经元的旁观者杀伤。
