A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia
A dual role of lipocalin 2 in the apoptosis and deramification of activated microglia
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DOI：
10.4049/jimmunol.179.5.3231
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Suk, Kyoungho
中科院分区：
文献类型：
--
作者：
Lee, Shinrye;Lee, Jayoung;Suk, Kyoungho
激活的小胶质细胞被认为会经历细胞凋亡作为一种自我调节机制。为了更好地了解小胶质细胞凋亡的分子机制，选择并表征了小胶质细胞的抗凋亡变体。在对 NO 诱导的细胞凋亡具有抵抗力的小胶质细胞中，脂质运载蛋白 2 (Icn2) 的表达显着下调。小胶质细胞中的炎症刺激会增加 lcn2 的表达。 Icn2 的稳定表达以及 rLCN2 蛋白的添加增强了小胶质细胞对 NO 诱导的细胞凋亡的敏感性，而使用短发夹 RNA 敲低 Icn2 的表达则减弱了细胞死亡。 Icn2 表达增加的小胶质细胞对其他细胞毒性药物也更敏感。因此;小胶质细胞的炎症激活可能导致 lc112 表达上调，从而使小胶质细胞对自我调节凋亡敏感。此外，BV-2小胶质细胞中lcn2的稳定表达诱导细胞形态变化为圆形，且突起消失。用 rLCN2 蛋白处理原代小胶质细胞培养物也诱导了小胶质细胞的脱枝。小胶质细胞的脱枝与细胞凋亡倾向密切相关，因为其他脱枝诱导剂如 cAMP 升高剂毛喉素、ATP 和钙离子载体也使小胶质细胞对细胞死亡更加敏感。综上所述，我们的结果表明，活化的小胶质细胞可能分泌 LCN2 蛋白，该蛋白以自分泌方式发挥作用，使小胶质细胞对自我调节细胞凋亡敏感，并赋予小胶质细胞变形虫形式，这是体内活化小胶质细胞的典型形态。
Activated microglia are thought to undergo apoptosis as a self-regulatory mechanism. To better understand molecular mechanisms of the microglial apoptosis, apoptosis-resistant variants of microglial cells were selected and characterized. The expression of lipocalin 2 (Icn2) was significantly down-regulated in the microglial cells that were resistant to NO-induced apoptosis. lcn2 expression was increased by inflammatory stimuli in microglia. The stable expression of Icn2 as well as the addition of rLCN2 protein augmented the sensitivity of microglia to the NO-induced apoptosis, while knockdown of Icn2 expression using short hairpin RNA attenuated the cell death. Microglial cells with increased Icn2 expression were more sensitive to other cytotoxic agents as well. Thus; inflammatory activation of microglia may lead to up-regulation of lc112 expression, which sensitizes microglia to the self-regulatory apoptosis. Additionally, the stable expression of lcn2 in BV-2 microglia cells induced a morphological change of the cells into the round shape with a loss of processes. Treatment of primary microglia cultures with the rLCN2 protein also induced the deramification of microglia. The deramitication of microglia was closely related with the apoptosis-prone phenotype, because other de ramification -inducing agents such as cAMP-elevating agent forskolin, ATP, and calcium ionophore also rendered microglia more sensitive to cell death. Taken together, our results suggest that activated microglia may secrete LCN2 protein, which act in an autocrine manner to sensitize microglia to the self-regulatory apoptosis and to endow microglia with an amoeboid form, a canonical morphology of activated microglia in vivo.