Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway
| Autor: | Xiao-Jie Zhao, Juan Wang, Teng-Fei Xue, Xiu-Lan Sun, Ji-Ye Huang, Juan Ji, Ruo-Bing Guo, Jin Yang, Xu-Dong Guo |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Lipopolysaccharides Aging autophagy Pyridines microglial polarization ATG5 Peroxisome proliferator-activated receptor Biology AMP-Activated Protein Kinases Protein Serine-Threonine Kinases Rats Sprague-Dawley Rosiglitazone 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Downregulation and upregulation AMP-Activated Protein Kinase Kinases medicine Animals Neuroinflammation Cells Cultured chemistry.chemical_classification Microglia Autophagy peroxisome proliferator‐activated receptor γ Cell Biology Original Articles Radicicol Cell biology Rats liver kinase B1 PPAR gamma 030104 developmental biology medicine.anatomical_structure chemistry Benzamides Original Article Signal transduction 030217 neurology & neurosurgery Signal Transduction |
| Zdroj: | Aging Cell |
| ISSN: | 1474-9726 |
| Popis: | Summary 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. |
| Databáze: | OpenAIRE |
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