FTY720 Modulates Microglia Toward Anti-inflammatory Phenotype by Suppressing Autophagy via STAT1 Pathway

Abstract

Since microglia-associated neuroinflammation plays a pivotal role in the progression of white matter diseases, modulating microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of fingolimod (FTY720) on microglia and analyzed the crosstalk between microglia autophagy and neuroinflammation. Lipopolysaccharide (LPS)-induced primary cultured microglia model was established. Microglial phenotypes were assessed by Western blot, quantitative real-time polymerase chain reaction (RT-PCR) and flow cytometry. Autophagy was evaluated by immunofluorescence, MDC staining and Western blot. Rapamycin was used to investigate the role of autophagic process in regulating microglial phenotypes. The signaling markers were screened by RT-PCR and Western blot. FTY720 shifted microglial phenotype from pro-inflammatory state to anti-inflammatory state and inhibited microglial autophagy under lipopolysaccharide (LPS) treatment. Rapamycin reversed the effect of FTY720 on phenotype transformation of microglia. The results of mechanism studies have shown that FTY720 notably repressed LPS-induced STAT1 activity, which was reactivated by rapamycin. Our research suggested that FTY720 could significantly transform pro-inflammatory microglia into anti-inflammatory microglia by suppressing autophagy via STAT1.

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Acknowledgements

This work was supported by National Natural Science Foundation of China (81571132, 81873743 to D.S., Tian, 81801223 to C. Qin) and Fundamental Research Funds for the Central Universities (2017KFYXJJ107 to D.S. Tian, 2017KFYXJJ124 to C. Qin)

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Hu, ZW., Zhou, LQ., Yang, S. et al. FTY720 Modulates Microglia Toward Anti-inflammatory Phenotype by Suppressing Autophagy via STAT1 Pathway. Cell Mol Neurobiol 41, 353–364 (2021). https://doi.org/10.1007/s10571-020-00856-9

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Keywords

  • FTY720
  • Microglia polarization
  • Autophagy
  • STAT1