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Antagonizing peroxisome proliferator-activated receptor ? facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway.

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 ? (PPAR?) agonist rosiglitazone prevents lipopolysaccharide (LPS)-induced microglial activation. Here, we observed that antagonizing PPAR? promoted LPS-stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPAR? antagonist T0070907 increased the expression of M2 markers, including CD206, IL-4, IGF-1, TGF-?1, TGF-?2, TGF-?3, G-CSF, and GM-CSF, and reduced the expression of M1 markers, such as CD86, Cox-2, iNOS, IL-1?, IL-6, TNF-?, IFN-?, and CCL2, thereby inhibiting NF?B-IKK? activation. Moreover, antagonizing PPAR? 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 PPAR? in BV2 microglial cells also activated LKB1-AMPK signaling and inhibited NF?B-IKK? activation, which are similar to the effects of antagonizing PPAR?. Taken together, our findings demonstrate that antagonizing PPAR? 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.

SUBMITTER: Ji J

PROVIDER: S-EPMC6052482 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Antagonizing peroxisome proliferator-activated receptor γ facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway.

Ji Juan J Xue Teng-Fei TF Guo Xu-Dong XD Yang Jin J Guo Ruo-Bing RB Wang Juan J Huang Ji-Ye JY Zhao Xiao-Jie XJ Sun Xiu-Lan XL

Aging cell 20180508 4

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 antago ...[more]

PMID: 29740932

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Project description:Microglia activation is recognized as the hallmark of neuroinflammation. However, the activation profile and phenotype changes of microglia during the process of retinal degeneration are poorly understood. This study aimed to elucidate the time-spatial pattern of microglia distribution and characterize the polarized phenotype of activated microglia during retinal neuroinflammation and degeneration in rd1 (Pde6?rd1/rd1) mice, the classic model of inherited retinal degeneration. Retinae of rd1 mice at different postnatal days (P7, P14, P21, P28, P56, and P180) were prepared for further analysis. We found most CD11b+ or IBA1+ microglia expressed Ki-67 and CD68 in rd1 mice and these cells migrated toward the layer of degenerative photoreceptors at the rapid rods degeneration phase from P14 to P28. These microglia exhibited typical ameboid activated shape with round bodies and scarce dendrites, while at late phase at P180, they displayed resting ramified morphology with elongated dendrites. Flow cytometry revealed that the percentage of CD86+CD206- M1 microglia increased markedly in rd1 retinae, however, no significant change was observed in CD206+CD86- M2 microglia. Interestingly, CD86+CD206+ microglia, an intermediate state between the two extremes of M1 and M2, increased markedly at the rapid rods degeneration phase. The immunofluorescence images revealed that microglia in rd1 mice highly expressed M1 markers including CD16/32, CD86, and CD40. In addition, increased expression of pro-inflammatory cytokines (TNF-?, IL-6, and CCL2) was observed in rd1 mice. Our findings unfolded a panorama for the first time that microglia conducted distinctive behaviors with the progression of retinal degeneration in rd1 mice. Microglia is activated and particularly polarized to a pro-inflammatory M1 phenotype at the rapid rods degenerative phase, suggesting that the involvement of M1 microglia in the retinal neuroinflammation and degeneration. Most microglia adopted an intermediate polarization "M1½" state in rd1, revealing that microglia orchestrated a complicated continuous spectrum in degenerative retina.

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Dataset Information

Antagonizing peroxisome proliferator-activated receptor ? facilitates M1-to-M2 shift of microglia by enhancing autophagy via the LKB1-AMPK signaling pathway.

Publications

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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