米诺环素选择性抑制小胶质细胞的 M1 极化。,Cell Death & Disease

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米诺环素选择性抑制小胶质细胞的 M1 极化。
Cell Death & Disease ( IF 8.1 ) Pub Date : 2013-Mar-07 , DOI: 10.1038/cddis.2013.54
K Kobayashi ₁ , S Imagama , T Ohgomori , K Hirano , K Uchimura , K Sakamoto , A Hirakawa , H Takeuchi , A Suzumura , N Ishiguro , K Kadomatsu

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米诺环素通常用于抑制小胶质细胞活化。人们普遍认为，活化的小胶质细胞具有双重功能，即促炎 (M1) 和抗炎 (M2) 功能。活化小胶质细胞的体内状态可能介于这两种极端状态之间。然而，调节小胶质细胞极性的机制仍然难以捉摸。在这里，我们针对米诺环素解决了这个问题。我们使用 SOD1(G93A) 小鼠作为模型，其表现出运动神经元特异性神经退行性疾病，肌萎缩侧索硬化。米诺环素的给药减弱了进展期 M1 小胶质细胞标志物表达的诱导，而它不影响早期发病阶段 M2 小胶质细胞标志物表达的瞬时增强。使用分别诱导 M1 或 M2 极化的脂多糖 (LPS) 或白介素 (IL)-4 刺激的原代培养小胶质细胞证实了这种选择性抑制作用。此外，米诺环素抑制 LPS 刺激的原代培养的小胶质细胞和 SOD1(G93A) 小鼠脊髓中 NF-κB 的上调。另一方面，IL-4 不诱导 NF-κB 的上调。该研究表明，米诺环素选择性抑制小胶质细胞极化至促炎状态，并为了解伴随小胶质细胞激活的许多疾病的发病机制提供基础。米诺环素抑制 LPS 刺激的原代培养的小胶质细胞和 SOD1(G93A) 小鼠脊髓中 NF-κB 的上调。另一方面，IL-4 不诱导 NF-κB 的上调。该研究表明，米诺环素选择性地抑制小胶质细胞极化至促炎状态，并为了解伴随小胶质细胞激活的许多疾病的发病机制提供基础。米诺环素抑制 LPS 刺激的原代培养的小胶质细胞和 SOD1(G93A) 小鼠脊髓中 NF-κB 的上调。另一方面，IL-4 不诱导 NF-κB 的上调。该研究表明，米诺环素选择性地抑制小胶质细胞极化至促炎状态，并为了解伴随小胶质细胞激活的许多疾病的发病机制提供基础。

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Minocycline selectively inhibits M1 polarization of microglia.

Minocycline is commonly used to inhibit microglial activation. It is widely accepted that activated microglia exert dual functions, that is, pro-inflammatory (M1) and anti-inflammatory (M2) functions. The in vivo status of activated microglia is probably on a continuum between these two extreme states. However, the mechanisms regulating microglial polarity remain elusive. Here, we addressed this question focusing on minocycline. We used SOD1(G93A) mice as a model, which exhibit the motor neuron-specific neurodegenerative disease, amyotrophic lateral sclerosis. Administration of minocycline attenuated the induction of the expression of M1 microglia markers during the progressive phase, whereas it did not affect the transient enhancement of expression of M2 microglia markers during the early pathogenesis phase. This selective inhibitory effect was confirmed using primary cultured microglia stimulated by lipopolysaccharide (LPS) or interleukin (IL)-4, which induced M1 or M2 polarization, respectively. Furthermore, minocycline inhibited the upregulation of NF-κB in the LPS-stimulated primary cultured microglia and in the spinal cord of SOD1(G93A) mice. On the other hand, IL-4 did not induce upregulation of NF-κB. This study indicates that minocycline selectively inhibits the microglia polarization to a proinflammatory state, and provides a basis for understanding pathogeneses of many diseases accompanied by microglial activation.

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