Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway.
Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway.
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拮抗过氧化物酶体增殖物激活受体 γ 通过 LKB1-AMPK 信号通路增强自噬，促进小胶质细胞 M1 向 M2 的转变
DOI：
10.1111/acel.12774
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发表时间：
2018-08
期刊：
影响因子：
7.8
通讯作者：
Sun XL
中科院分区：
文献类型：
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作者：
Ji J;Xue TF;Guo XD;Yang J;Guo RB;Wang J;Huang JY;Zhao XJ;Sun XL
由于不同的小胶质细胞表型，小胶质细胞介导的神经炎症在各种脑部疾病中起双重作用，包括有害的M1和神经保护性M2。越来越多的证据表明，过氧化物酶体增殖物激活受体γ（PPARγ）激动剂罗格列酮可阻止脂多糖（LPS）诱导的小胶质细胞活化。在这里，我们观察到拮抗PPARγ促进LPS刺激的原代小胶质细胞从M1表型到M2表型的极化变化。PPARγ拮抗剂T0070907可增加M2标志物（包括CD 206、IL-4、IGF-1、TGF-β1、TGF-β2、TGF-β3、G-CSF和GM-CSF）的表达，降低M1标志物（如CD 86、考克斯-2、iNOS、IL-1β、IL-6、TNF-α、IFN-γ和CCL 2）的表达，从而抑制NFκB-IKKβ活化。此外，拮抗PPARγ促进小胶质细胞自噬，如P62下调和Beclin 1，Atg 5和LC 3-II/LC 3-I上调所示，从而增强自噬体的形成及其在小胶质细胞中被溶酶体降解。此外，我们发现LKB 1-STRAD-MO 25复合物形成的增加增强了自噬。LKB 1抑制剂根赤霉素或敲低LKB 1阻止了T0070907的自噬改善和M1至M2表型转变。同时，我们发现在BV 2小胶质细胞中敲低PPARγ也激活了LKB 1-AMPK信号通路，抑制了NFκB-IKKβ的激活，这与拮抗PPARγ的作用相似。总之，我们的研究结果表明，拮抗PPARγ促进LPS诱导的小胶质细胞中M1-M2表型转变，这可能是由于通过激活LKB 1-AMPK信号通路改善自噬。
Microglia‐mediated neuroinflammation plays a dual role in various brain diseases due to distinct microglial phenotypes, including deleterious M1 and neuroprotective M2. There is growing evidence that the peroxisome proliferator‐activated receptor γ (PPARγ) agonist rosiglitazone prevents lipopolysaccharide (LPS)‐induced microglial activation. Here, we observed that antagonizing PPARγ promoted LPS‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARγ antagonist T0070907 increased the expression of M2 markers, including CD206, IL‐4, IGF‐1, TGF‐β1, TGF‐β2, TGF‐β3, G‐CSF, and GM‐CSF, and reduced the expression of M1 markers, such as CD86, Cox‐2, iNOS, IL‐1β, IL‐6, TNF‐α, IFN‐γ, and CCL2, thereby inhibiting NFκB–IKKβ activation. Moreover, antagonizing PPARγ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC3‐II/LC3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB1–STRAD–MO25 complex formation enhances autophagy. The LKB1 inhibitor radicicol or knocking down LKB1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPARγ in BV2 microglial cells also activated LKB1–AMPK signaling and inhibited NFκB–IKKβ activation, which are similar to the effects of antagonizing PPARγ. Taken together, our findings demonstrate that antagonizing PPARγ promotes the M1‐to‐M2 phenotypic shift in LPS‐induced microglia, which might be due to improved autophagy via the activation of the LKB1–AMPK signaling pathway.
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影响因子：
12.8
作者：
Jeon SM
通讯作者：
Jeon SM
AMP激活的蛋白激酶对ULK1（HATG1）的磷酸化将能量传感连接到线粒体。
DOI：
10.1126/science.1196371
发表时间：
2011-01-28
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Egan DF;Shackelford DB;Mihaylova MM;Gelino S;Kohnz RA;Mair W;Vasquez DS;Joshi A;Gwinn DM;Taylor R;Asara JM;Fitzpatrick J;Dillin A;Viollet B;Kundu M;Hansen M;Shaw RJ
通讯作者：
Shaw RJ
影响因子：
3.9
作者：
Liu, Shenglan;Chen, Shaorui;Jiang, Jianmin
通讯作者：
Jiang, Jianmin
DOI：
10.1523/jneurosci.5268-11.2012
发表时间：
2012-07-25
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Mandrekar-Colucci S;Karlo JC;Landreth GE
通讯作者：
Landreth GE
影响因子：
21.3
作者：
通讯作者：
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