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Updated: Nov 23, 2025
Three-dimensional Confocal Analysis of Microglia/macrophage Markers of Polarization in Experimental Brain Injury
Published on: September 4, 2013
DJ-1 Regulates Microglial Polarization Through P62-Mediated TRAF6/IRF5 Signaling in Cerebral Ischemia-Reperfusion
Tingting Wang1,2,3, Na Zhao1,2,3, Li Peng1,2,3
1Department of Pathology, Chongqing Medical University, Chongqing, China.
Abstract:
The polarization of microglia/macrophage, the resident immune cells in the brain, plays an important role in the injury and repair associated with ischemia-reperfusion (I/R). Previous studies have shown that DJ-1 has a protective effect in cerebral I/R. We found that DJ-1 regulates the polarization of microglial cells/macrophages after cerebral I/R and explored the mechanism by which DJ-1 mediates microglial/macrophage polarization in cerebral I/R. Middle cerebral artery occlusion/reperfusion (MCAO/R) and oxygen and glucose deprivation/reoxygenation (OGD/R) models were used to simulate cerebral I/R in vivo and in vitro, respectively. DJ-1 siRNA and the DJ-1-based polypeptide ND13 were used to produce an effect on DJ-1, and the P62-specific inhibitor XRK3F2 was used to block the effect of P62. Enhancing the expression of DJ-1 induced anti-inflammatory (M2) polarization of microglia/macrophage, and the expression of the anti-inflammatory factors IL-10 and IL-4 increased. Interference with DJ-1 expression induced pro-inflammatory (M1) polarization of microglia/macrophage, and the expression of the proinflammatory factors TNF-α and IL-1β increased. DJ-1 inhibited the expression of P62, impeded the interaction between P62 and TRAF6, and blocked nuclear entry of IRF5. In subsequent experiments, XRK3F2 synergistically promoted the effect of DJ-1 on microglial/macrophage polarization, further attenuating the interaction between P62 and TRAF6.
Insights
DJ-1 protein regulates brain immune cell polarization after ischemic stroke, promoting repair by reducing inflammation. This finding offers new therapeutic targets for cerebral ischemia-reperfusion injury.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglia/macrophage polarization is crucial in brain injury and repair following ischemia-reperfusion (I/R).
- DJ-1 protein has demonstrated protective effects in cerebral I/R models.
- Understanding DJ-1's role in microglial/macrophage polarization is key to developing targeted therapies.
Purpose of the Study:
- To investigate how DJ-1 influences microglial/macrophage polarization in cerebral I/R.
- To elucidate the underlying molecular mechanisms by which DJ-1 mediates this polarization.
Main Methods:
- Cerebral I/R was simulated using middle cerebral artery occlusion/reperfusion (MCAO/R) in vivo and oxygen/glucose deprivation/reoxygenation (OGD/R) in vitro.
- DJ-1 expression was modulated using siRNA and a polypeptide (ND13).
- A P62-specific inhibitor (XRK3F2) was employed to block P62 activity.
Main Results:
- Increased DJ-1 expression promoted anti-inflammatory (M2) polarization and elevated IL-10 and IL-4 levels.
- Reduced DJ-1 expression induced pro-inflammatory (M1) polarization, increasing TNF-α and IL-1β.
- DJ-1 inhibited P62, disrupted P62-TRAF6 interaction, and blocked IRF5 nuclear entry.
- XRK3F2 enhanced DJ-1's effect on polarization and further reduced P62-TRAF6 interaction.
Conclusions:
- DJ-1 plays a significant role in regulating microglial/macrophage polarization during cerebral I/R.
- DJ-1 exerts its effects by inhibiting P62, thereby modulating the P62-TRAF6-IRF5 pathway.
- Targeting DJ-1 presents a promising therapeutic strategy for mitigating neuroinflammation and promoting recovery after stroke.
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