Department of Pathology, School of Medicine, University of Virginia Charlottesville, VA, USA ; Medical Scientist Training Program, School of Medicine, University of Virginia Charlottesville, VA, USA ; Neuroscience Graduate Program, School of Medicine, University of Virginia Charlottesville, VA, USA.
Department of Pathology, School of Medicine, University of Virginia Charlottesville, VA, USA.
Front Cell Neurosci. 2014 Nov 7;8:360. doi: 10.3389/fncel.2014.00360. eCollection 2014.
Apoptotic neurons generated during normal brain development or secondary to pathologic insults are efficiently cleared from the central nervous system. Several soluble factors, including nucleotides, cytokines, and chemokines are released from injured neurons, signaling microglia to find and clear debris. One such chemokine that serves as a neuronal-microglial communication factor is fractalkine, with roles demonstrated in several models of adult neurological disorders. Lacking, however, are studies investigating roles for fractalkine in perinatal brain injury, an important clinical problem with no effective therapies. We used a well-characterized mouse model of ethanol-induced apoptosis to assess the role of fractalkine in neuronal-microglial signaling. Quantification of apoptotic debris in fractalkine-knockout (KO) and CX3CR1-KO mice following ethanol treatment revealed increased apoptotic bodies compared to wild type mice. Ethanol-induced injury led to release of soluble, extracellular fractalkine. The extracellular media harvested from apoptotic brains induces microglial migration in a fractalkine-dependent manner that is prevented by neutralization of fractalkine with a blocking antibody or by deficiency in the receptor, CX3CR1. This suggests fractalkine acts as a "find-me" signal, recruiting microglial processes toward apoptotic cells to promote their clearance. Next, we aimed to determine whether there are downstream alterations in cytokine gene expression due to fractalkine signaling. We examined mRNA expression in fractalkine-KO and CX3CR1-KO mice after alcohol-induced apoptosis and found differences in cytokine production in the brains of these KOs by 6 h after ethanol treatment. Collectively, this suggests that fractalkine acts as a "find me" signal released by apoptotic neurons, and subsequently plays a critical role in modulating both clearance and inflammatory cytokine gene expression after ethanol-induced apoptosis.
在正常的大脑发育过程中或继发于病理损伤的情况下，凋亡神经元会被中枢神经系统有效地清除。几种可溶性因子，包括核苷酸、细胞因子和趋化因子，从受损神经元中释放出来，向小胶质细胞发出信号，指示其寻找并清除碎片。趋化因子中的一种，即 fractalkine，作为神经元-小胶质细胞通讯因子，在几种成人神经紊乱模型中发挥作用。然而，在围产期脑损伤中，缺乏 fractalkine 的研究，这是一个没有有效治疗方法的重要临床问题。我们使用了一种经过充分表征的乙醇诱导凋亡的小鼠模型，来评估 fractalkine 在神经元-小胶质细胞信号中的作用。在乙醇处理后，对 fractalkine 敲除（KO）和 CX3CR1-KO 小鼠中的凋亡碎片进行定量，结果显示与野生型小鼠相比，凋亡小体增加。乙醇诱导的损伤导致可溶的细胞外 fractalkine 释放。从凋亡脑中提取的细胞外介质以 fractalkine 依赖的方式诱导小胶质细胞迁移，这种迁移可被阻断 fractalkine 的中和抗体或受体 CX3CR1 的缺失所阻止。这表明 fractalkine 作为一种“寻找我”信号，将小胶质细胞的突起招募到凋亡细胞上，促进其清除。接下来，我们旨在确定 fractalkine 信号是否会导致下游细胞因子基因表达发生改变。我们在乙醇诱导凋亡后检查了 fractalkine-KO 和 CX3CR1-KO 小鼠中的 mRNA 表达，发现这些 KO 小鼠在乙醇处理后 6 小时大脑中的细胞因子产生存在差异。综上所述，这表明 fractalkine 作为一种由凋亡神经元释放的“寻找我”信号，随后在乙醇诱导的凋亡后，在调节清除和炎症细胞因子基因表达方面发挥关键作用。
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