Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson's disease.
Kir6.1/K-ATP channel modulates microglia phenotypes: implication in Parkinson's disease.
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Kir6.1/K-ATP 通道调节小胶质细胞表型：对帕金森病的影响
DOI：
10.1038/s41419-018-0437-9
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发表时间：
2018-03-14
影响因子：
9
通讯作者：
Hu G
中科院分区：
文献类型：
--
作者：
Du RH;Sun HB;Hu ZL;Lu M;Ding JH;Hu G
经典激活（M1表型）和交替激活（M2表型）是小胶质细胞激活状态的两个极端，在帕金森病（PD）的免疫发病机制中可产生神经毒性或神经保护作用。通过调节小胶质细胞的极化状态来开发其有益特性为PD的治疗提供了巨大的潜力。然而，调节小胶质细胞极化的机制仍然难以捉摸。在这里，我们证明了Kir6.1-含ATP敏感性钾（Kir6.1/K-ATP）通道转换小胶质细胞从有害的M1表型到有益的M2表型。Kir6.1敲低抑制M2极化，同时加剧M1小胶质细胞的炎症反应，而Kir6.1过表达促进M2极化，同时减轻M1小胶质细胞极化的毒性相。此外，我们观察到Kir6.1缺陷显著加剧了PD小鼠模型中多巴胺能神经元的死亡，伴随着小胶质细胞的激活。在机制上，Kir6.1缺陷增强了PD模型小鼠黑质中p38 MAPK-NF-κB通路的激活，并增加了M1/M2标记物的比例。体内p38 MAPK的抑制部分挽救了Kir6.1消融对小胶质细胞表型和多巴胺能神经元死亡的有害影响。综上所述，Kir6.1/K-ATP通道通过抑制p38 MAPK-NF-κB信号通路调节小胶质细胞表型转化，可能成为PD治疗的一个新靶点。
Classical activation (M1 phenotype) and alternative activation (M2 phenotype) are the two polars of microglial activation states that can produce either neurotoxic or neuroprotective effects in the immune pathogenesis of Parkinson’s disease (PD). Exploiting the beneficial properties of microglia cells by modulating their polarization states provides great potential for the treatment of PD. However, the mechanism that regulates microglia polarization remains elusive. Here we demonstrated that Kir6.1-containing ATP-sensitive potassium (Kir6.1/K-ATP) channel switched microglia from the detrimental M1 phenotype toward the beneficial M2 phenotype. Kir6.1 knockdown inhibited M2 polarization and simultaneously exaggerated M1 microglial inflammatory responses, while Kir6.1 overexpression promoted M2 polarization and synchronously alleviated the toxic phase of M1 microglia polarization. Furthermore, we observed that the Kir6.1 deficiency dramatically exacerbated dopaminergic neuron death companied by microglia activation in mouse model of PD. Mechanistically, Kir6.1 deficiency enhanced the activation of p38 MAPK–NF-κB pathway and increased the ratio of M1/M2 markers in the substantia nigra compacta of mouse model of PD. Suppression of p38 MAPK in vivo partially rescued the deleterious effects of Kir6.1 ablation on microglia phenotype and dopaminergic neuron death. Collectively, our findings reveal that Kir6.1/K-ATP channel modulates microglia phenotypes transition via inhibition of p38 MAPK–NF-κB signaling pathway and Kir6.1/K-ATP channel may be a promising therapeutic target for PD.
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影响因子：
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