Translocator protein (18 kDa)/peripheral benzodiazepine receptor specific ligands induce microglia functions consistent with an activated state.
Translocator protein (18 kDa)/peripheral benzodiazepine receptor specific ligands induce microglia functions consistent with an activated state.
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DOI：
10.1002/glia.21091
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发表时间：
2011-02
期刊：
影响因子：
6.2
通讯作者：
Guilarte, Tomas R.
中科院分区：
文献类型：
--
作者：
Choi, Judy;Ifuku, Masataka;Noda, Mami;Guilarte, Tomas R.
在大脑中，转运蛋白(18 KDa)(TSPO)，以前被称为外周苯二氮卓类受体(PBR)，是一种神经胶质蛋白，被广泛用作脑损伤和炎症的生物标志物。然而，TSPO在胶质细胞中的功能作用还没有得到很好的描述。在这项研究中，我们发现TSPO特异性配体R-PK11195(Pk)和Ro5-4864(Ro)促进了小胶质细胞的增殖和吞噬功能，但对迁移没有影响。两种配体均能增加细胞内ROS的产生，这种作用可能是通过NADPH-氧化酶来实现的。PK和Ro也使IL-1β释放略有增加，但可检测到。我们还检测了PK和Ro对内毒素(LPS)和三磷酸腺苷(ATP)激活的小胶质细胞促炎基因表达和细胞因子释放的影响。PK或Ro对内毒素诱导的促炎基因表达无影响，但均可降低ATP诱导的COX-2基因表达。RO可促进内毒素诱导的IL-1β的释放，而PK则无此作用。但Ro可降低三磷酸腺苷诱导的IL-1β和肿瘤坏死因子-α的释放，PK可降低三磷酸腺苷诱导的肿瘤坏死因子-α的释放。在脂多糖存在的情况下暴露于Ro可增加小胶质细胞的凋亡数，这一作用可被PK阻断。这些发现表明，TSPO配体调节与小胶质细胞激活一致的细胞功能。此外，当小胶质细胞被激活时，这些配体可能通过减少促炎基因的表达和细胞因子的释放而具有治疗潜力。最后，类Ro配体可能参与通过细胞凋亡消除激活的小胶质细胞。
In the brain, translocator protein (18 kDa) (TSPO), previously called peripheral benzodiazepine receptor (PBR), is a glial protein that has been extensively used as a biomarker of brain injury and inflammation. However, the functional role of TSPO in glial cells is not well characterized. In this study, we show that the TSPO-specific ligands R-PK11195 (PK) and Ro5-4864 (Ro) increased microglia proliferation and phagocytosis with no effect on migration. Both ligands increased reactive oxygen species (ROS) production, and this effect may be mediated by NADPH-oxidase. PK and Ro also produced a small but detectable increase in IL-1β release. We also examined the effect of PK and Ro on the expression of pro-inflammatory genes and cytokine release in lipopolysaccharide (LPS) and adenosine triphosphate (ATP) activated microglia. PK or Ro had no effect on LPS-induced increase of pro-inflammatory genes, but they both decreased the ATP-induced increase of COX-2 gene expression. Ro, but not PK, enhanced the LPS-induced release of IL-1β. However, Ro decreased the ATP-induced release of IL-1β and TNF-α, and PK decreased the ATP-induced release of TNF-α. Exposure to Ro in the presence of LPS increased the number of apoptotic microglia, an effect that could be blocked by PK. These findings show that TSPO ligands modulate cellular functions consistent with microglia activation. Further, when microglia are activated, these ligands may have therapeutic potential by reducing the expression of pro-inflammatory genes and cytokine release. Finally, Ro-like ligands may be involved in the elimination of activated microglia via apoptosis.
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