期刊
AGING CELL
卷 17, 期 4, 页码 -出版社
WILEY
DOI: 10.1111/acel.12774
关键词
autophagy; liver kinase B1; microglial polarization; peroxisome proliferator-activated receptor gamma
资金
- National Natural Science Foundation of China [81473197, 81773701, 81273495]
- Jiangsu Key Research and Development Program [BE2017737]
- 333 high-level talents project of Jiangsu Province [BRA2017469]
- China Postdoctoral Science Foundation [172436]
- Postgraduate Research & Practice Innovation Program of Jiangsu Province [KYCX17_1271]
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 gamma (PPAR gamma) agonist rosiglitazone prevents lipopolysaccharide (LPS)-induced microglial activation. Here, we observed that antagonizing PPARc promoted LPS-stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPARc antagonist T0070907 increased the expression of M2 markers, including CD206, IL-4, IGF-beta 1, TGF-beta 1, TGF-beta 2, TGF-beta 3, G-CSF, and GM-CSF, and reduced the expression of M1 markers, such as CD86, Cox-2, iNOS, IL-1 beta, IL-6, TNF-alpha, IFN-gamma, and CCL2, thereby inhibiting NFj kappa B-IKK beta activation. Moreover, antagonizing PPARc 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 PPARc in BV2 microglial cells also activated LKB1-AMPK signaling and inhibited NF kappa B-IKK beta activation, which are similar to the effects of antagonizing PPAR gamma. Taken together, our findings demonstrate that antagonizing PPARc 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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