Antagonizing peroxisome proliferator‐activated receptor γ facilitates M1‐to‐M2 shift of microglia by enhancing autophagy via the LKB 1– AMPK signaling pathway

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 ( PPAR γ) agonist rosiglitazone prevents lipopolysaccharide ( LPS )‐induced microglial activation. Here, we observed that antagonizing PPAR γ promoted LPS ‐stimulated changes in polarization from the M1 to the M2 phenotype in primary microglia. PPAR γ antagonist T0070907 increased the expression of M2 markers, including CD 206, IL ‐4, IGF ‐1, TGF ‐β1, TGF ‐β2, TGF ‐β3, G‐ CSF , and GM ‐ CSF , and reduced the expression of M1 markers, such as CD 86, Cox‐2, iNOS , IL ‐1β, IL ‐6, TNF ‐α, IFN ‐γ, and CCL 2, thereby inhibiting NF κB– IKK β activation. Moreover, antagonizing PPAR γ promoted microglial autophagy, as indicated by the downregulation of P62 and the upregulation of Beclin1, Atg5, and LC 3‐ II / LC 3‐I, thereby enhancing the formation of autophagosomes and their degradation by lysosomes in microglia. Furthermore, we found that an increase in LKB 1– STRAD – MO 25 complex formation enhances autophagy. The LKB 1 inhibitor radicicol or knocking down LKB 1 prevented autophagy improvement and the M1‐to‐M2 phenotype shift by T0070907. Simultaneously, we found that knocking down PPAR γ in BV 2 microglial cells also activated LKB 1– AMPK signaling and inhibited NF κB– IKK β activation, which are similar to the effects of antagonizing PPAR γ. Taken together, our findings demonstrate that antagonizing PPAR γ promotes the M1‐to‐M2 phenotypic shift in LPS ‐induced microglia, which might be due to improved autophagy via the activation of the LKB 1– AMPK signaling pathway.