Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.
Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.
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发育中的大鼠小脑中雌二醇和前列腺素 E2 对小胶质细胞吞噬作用的调节控制。
DOI：
10.1007/s12311-019-01071-z
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发表时间：
2019
期刊：
影响因子：
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通讯作者：
McCarthy,MargaretM
中科院分区：
文献类型：
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作者：
Perez-Pouchoulen,Miguel;Yu,StaceyJ;Roby,ClintonR;Bonsavage,Nicole;McCarthy,MargaretM
小胶质细胞对发育中的大脑至关重要，它们部分通过吞噬过程实现这一目标，吞噬过程受与细胞死亡和突触连接相关的微环境信号调节。在大鼠小脑中，小胶质细胞吞噬在出生后发育的第三周达到最高活性，但调节这种活性的因素尚不清楚。前列腺素E2（PGE2）刺激雌激素合成酶芳香化酶的信号通路在出生后第二周达到峰值，是浦肯野细胞成熟的关键调节因子。我们探讨了pge2 -雌二醇通路与成熟小脑小胶质细胞的关系。为此，我们用雌二醇和pge2合成的药理学抑制剂治疗发育中的大鼠幼鼠，然后用通用标记物Iba1染色小胶质细胞，并量化蚓部和小脑半球参与吞噬和吞噬杯的小胶质细胞。在出生后第17天，抑制芳香化酶减少了蚓部吞噬杯的数量，但在小脑半球没有。尼美舒利和吲哚美辛对pge2生成酶环加氧酶1和2的抑制作用也有类似的结果。相比之下，雌二醇或pge2治疗对发育中的小脑的小胶质细胞吞噬作用几乎没有影响。因此，内源性雌激素和前列腺素在出生后小脑发育的一个选择窗口期上调小胶质细胞的吞噬活性，但用这些相同的信号分子进行外源性治疗不会进一步增加已经很高的吞噬水平。这可能是由于较高的阈值或抵抗外源扰动的证据。
Microglia are essential to sculpting the developing brain, and they achieve this in part through the process of phagocytosis which is regulated by microenvironmental signals associated with cell death and synaptic connectivity. In the rat cerebellum, microglial phagocytosis reaches its highest activity during the third postnatal week of development but the factors regulating this activity are unknown. A signaling pathway, involving prostaglandin E2(PGE2) stimulation of the estrogen synthetic enzyme aromatase, peaks during the 2nd postnatal week and is a critical regulator of Purkinje cell maturation. We explored the relationship between the PGE2-estradiol pathway and microglia in the maturing cerebellum. Toward that end, we treated developing rat pups with pharmacological inhibitors of estradiol and PGE2synthesis and then stained microglia with the universal marker Iba1 and quantified microglia engaged in phagocytosis as well as phagocytic cups in the vermis and cerebellar hemispheres. Inhibition of aromatase reduced the number of phagocytic cups in the vermis, but not in the cerebellar hemisphere at postnatal day 17. Similar results were found after treatment with nimesulide and indomethacin, inhibitors of the PGE2-producing enzymes cyclooxygenase 1 and 2. In contrast, treatment with estradiol or PGE2had little effect on microglial phagocytosis in the developing cerebellum. Thus, endogenous estrogens and prostaglandins upregulate the phagocytic activity of microglia during a select window of postnatal cerebellar development, but exogenous treatment with these same signaling molecules does not further increase the already high levels of phagocytosis. This may be due to an upper threshold or evidence of resistance to exogenous perturbation.