DJ-1 activates the Atg5-Atg12-Atg16L1 complex via Sirt1 to influence microglial polarization and alleviate cerebral ischemia/reperfusion-induced inflammatory injury

  • Neurochem Int. 2022 Jul;157:105341. doi: 10.1016/j.neuint.2022.105341.
Na Zhao  1 ,  Yumei Li  2 ,  Chenglong Wang  3 ,  Ying Xue  2 ,  Li Peng  2 ,  Tingting Wang  2 ,  Yong Zhao  2 ,  Ge Xu  4 ,  Shanshan Yu  5
Affiliations
  • 1. Department of Pathology, College of Basic Medicine, Chongqing Medical University, 400016, Chongqing, PR China; Chengdu Second People's Hospital, 610000, Chengdu, PR China.
  • 2. Department of Pathology, College of Basic Medicine, Chongqing Medical University, 400016, Chongqing, PR China.
  • 3. Department of Pathology, College of Basic Medicine, Chongqing Medical University, 400016, Chongqing, PR China; Department of Pathology, Chongqing Hospital of Traditional Chinese Medicine, 400021, Chongqing, PR China.
  • 4. Institute of Life Sciences, Chongqing Medical University, 400016, Chongqing, PR China.
  • 5. Department of Pathology, College of Basic Medicine, Chongqing Medical University, 400016, Chongqing, PR China. Electronic address: [email protected].
PMID: 35429577 DOI: 10.1016/j.neuint.2022.105341
Abstract

Background: After cerebral ischemia/reperfusion (I/R) injury, activated microglia can be polarized towards different phenotypes (the proinflammatory M1 phenotype or the anti-inflammatory M2 phenotype) to regulate neuroinflammation. Our previous research showed that DJ-1 has anti-inflammatory effects in cerebral I/R. Here, we examined whether the neuroprotective effect of DJ-1 is related to the autophagy-associated Atg5-Atg12-Atg161L1 complex and whether SIRT1 is involved in the influence of DJ-1 by mediating microglial polarization and ameliorating cerebral I/R injury.

Methods: To answer these questions, we adopted the middle cerebral artery occlusion/reperfusion (MCAO/R) model to simulate I/R injury, knocked down the expression of DJ-1 with siRNA, and used the chemical inhibitor EX-527 to inhibit the expression of SIRT1. Related indexes were evaluated by Western blotting, immunoprecipitation and transmission electron microscopy.

Results: Interference with DJ-1 promotes the polarization of microglia from the anti-inflammatory phenotype to the proinflammatory phenotype. Addition of a SIRT1 Inhibitor following DJ-1 interference enhances the effect of DJ-1 interference on microglial polarization, decreases the level of the Atg5-Atg12-Atg16L1 complex, and inhibits Autophagy.

Conclusion: These results suggest that DJ-1 regulates the polarization of microglia during cerebral I/R injury, possibly by activating the Atg5-Atg12-Atg16L1 complex through SIRT1 to promote Autophagy.

Keywords
Atg5-Atg12-Atg16L1; Autophagy; Cerebral I/R injury; DJ-1; Microglial polarization; Sirt1.
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