Antagonizing Peroxisome Proliferator-Activated Receptor γ Facilitates M1-to-M2 Shift of Microglia by Enhancing Autophagy via the LKB1-AMPK Signaling Pathway

Juan Ji, Teng-Fei Xue, Xu-Dong Guo, Jin Yang, Ruo-Bing Guo, Juan Wang, Ji-Ye Huang, Xiao-Jie Zhao, Xiu-Lan Sun

Aging Cell. 2018 Aug;17(4):e12774.

PMID: 29740932

Abstract:

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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP313516664	T0070907		313516-66-4	Price