Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis
Photoreceptor outer segment phagocytosis attenuates oxidative stress-induced apoptosis with concomitant neuroprotectin D1 synthesis
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DOI：
10.1073/pnas.0705963104
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发表时间：
2007-08-07
影响因子：
11.1
通讯作者：
Bazan, Nicolas G.
中科院分区：
文献类型：
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作者：
Mukherjee, Pranab K.;Marcheselli, Victor L.;Bazan, Nicolas G.
光感受器细胞（视杆细胞和视锥细胞）的更新伴随着外节的远端尖端的间歇性脱落，随后是它们在视网膜色素上皮（RPE）细胞中的吞噬作用。这种更新对视力至关重要，并且认为它促进了光感受器和RPE细胞的存活。然而，没有具体的生存信使/调解人尚未确定。我们在这里表明，光感受器外节（POS）的吞噬作用显着减弱氧化应激诱导的ARPE-19细胞在文化中的凋亡。这种现象似乎不是吞噬作用的普遍结果，因为非生物性（聚苯乙烯微球）吞噬作用不引起保护。游离二十二碳六烯酸（DHA）池的大小和神经保护素D1（NPD 1）的含量增加POS吞噬，但在微球吞噬。我们还探索了在这些条件下的其他脂质介质[脂氧素A4和15（5）-和12（S）-羟基二十碳四烯酸]，发现它们在POS吞噬作用下没有变化。此外，对经历POS吞噬的RPE细胞的氧化应激挑战进一步增加DHA和NPD 1含量。在这些条件下，在RPE细胞内以及在培养基中发现NPD 1，表明自分泌和旁分泌生物活性。此外，使用氘标记的DHA，我们表明，随着氧化应激期间游离DHA的可用性增加，ARPE-19细胞中的NPD 1合成增加。我们的数据表明，在吞噬过程中，通过增强NPD 1的合成，促进光受体和RPE细胞的存活的独特信号传导。两者合计，NPD 1可能是一种介质，促进稳态调节感光细胞更新过程中的细胞完整性。
Photoreceptor cell (rods and cones) renewal is accompanied by intermittent shedding of the distal tips of the outer segment followed by their phagocytosis in the retinal pigment epithelial (RPE) cells. This renewal is essential for vision, and it is thought that it fosters survival of photoreceptors and of RPE cells. However, no specific survival messenger/mediators have as yet been identified. We show here that photoreceptor outer segment (POS) phagocytosis markedly attenuates oxidative stress-induced apoptosis in ARPE-19 cells in culture. This phenomenon does not seem to be a generalized outcome of phagocytosis because nonbiological (polystyrene microsphere) phagocytosis did not elicit protection. The free docosahexaenoic acid (DHA) pool size and neuroprotectin D1 (NPD1) content increased during POS phagocytosis but not during microspheres phagocytosis. We have also explored other lipid mediators [lipoxin A4 and 15(5)- and 12(S)-hydroxyeicosatetraenoic acids] under these conditions and found them unchanged upon POS phagocytosis. Moreover, oxidative stress challenge to RPE cells undergoing POS phagocytosis further increased DHA and NPD1 content. Under these conditions, NPD1 was found within the RPE cells as well as in the culture medium, suggesting autocrine and paracrine bioactivity. Furthermore, using deuterium-labeled DHA, we show that as the availability of free DHA increases during oxidative stress, NPD1 synthesis is augmented in ARPE-19 cells. Our data suggest a distinct signaling that promotes survival of photo- receptor and RPE cells by enhancing the synthesis of NPD1 during phagocytosis. Taken together, NPD1 may be a mediator that promotes homeostatic regulation of cell integrity during photoreceptor cell renewal.