Effects of 3,3′, 5-Triiodothyronine on Microglial Functions
Effects of 3,3′, 5-Triiodothyronine on Microglial Functions
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DOI：
10.1002/glia.22792
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发表时间：
2015-05-01
期刊：
影响因子：
6.2
通讯作者：
Noda, Mami
中科院分区：
文献类型：
--
作者：
Mori, Yuki;Tomonaga, Daichi;Noda, Mami
l-三碘甲状腺原氨酸（3，3 '，5-triiodothyronine; T3）是甲状腺激素（TH）的活性形式，对于CNS的发育和功能是必需的。虽然TH的非基因组效应，其质膜结合受体，其信号转导已被确定，在中枢神经系统的每种细胞类型的精确功能仍有待研究。通过小胶质细胞吞噬作用清除细胞碎片和凋亡细胞是修复受损神经元-胶质细胞网络的关键步骤。在这里，我们报告T3对小胶质细胞功能的非基因组效应。暴露于T3增加迁移，膜皱褶和吞噬原代培养的小鼠小胶质细胞。在体内，T3注射与刺伤一起吸引更多的小胶质细胞到损伤部位。阻断TH转运体和受体（TRs）或TR-knock-out（KO）抑制T3诱导的小胶质细胞迁移和形态学变化。通过抑制G（i/o）蛋白和NO合成酶以及随后的信号传导如磷酸肌醇3-激酶（PI 3 K）、丝裂原活化蛋白激酶（MAPK）/细胞外信号调节激酶（ERK）来减弱T3诱导的小胶质细胞迁移或膜皱褶。Na+/K+-ATP酶、Na+/Ca 2+交换器（NCX）反向模式和小电导Ca 2+依赖性K+（SK）通道的抑制剂也可减弱小胶质细胞的迁移或吞噬作用。有趣的是，T3诱导的小胶质细胞迁移，而不是吞噬作用，依赖于GABA（A）和GABA（B）受体，虽然GABA本身并不影响迁移能力。我们的研究结果表明，T3通过多种复杂的机制调节小胶质细胞的多种功能反应，这可能有助于CNS的生理和/或病理生理功能。GLIA 2015：63：906-920
l-tri-iodothyronine (3, 3', 5-triiodothyronine; T3) is an active form of the thyroid hormone (TH) essential for the development and function of the CNS. Though nongenomic effect of TH, its plasma membrane-bound receptor, and its signaling has been identified, precise function in each cell type of the CNS remained to be investigated. Clearance of cell debris and apoptotic cells by microglia phagocytosis is a critical step for the restoration of damaged neuron-glia networks. Here we report nongenomic effects of T3 on microglial functions. Exposure to T3 increased migration, membrane ruffling and phagocytosis of primary cultured mouse microglia. Injection of T3 together with stab wound attracted more microglia to the lesion site in vivo. Blocking TH transporters and receptors (TRs) or TR-knock-out (KO) suppressed T3-induced microglial migration and morphological change. The T3-induced microglial migration or membrane ruffling was attenuated by inhibiting G(i/o)-protein as well as NO synthase, and subsequent signaling such as phosphoinositide 3-kinase (PI3K), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK). Inhibitors for Na+/K+-ATPase, reverse mode of Na+/Ca2+ exchanger (NCX), and small-conductance Ca2+-dependent K+ (SK) channel also attenuated microglial migration or phagocytosis. Interestingly, T3-induced microglial migration, but not phagocytosis, was dependent on GABA(A) and GABA(B) receptors, though GABA itself did not affect migratory aptitude. Our results demonstrate that T3 modulates multiple functional responses of microglia via multiple complex mechanisms, which may contribute to physiological and/or pathophysiological functions of the CNS. GLIA 2015:63:906-920