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Published on: March 1, 2019
Transcription Factor Forkhead Box P (Foxp) 1 Reduces Brain Damage During Cerebral Ischemia-Reperfusion Injury in Mice
Yang Li1, Yang Changhong2, Yang Liyu3
1Department of Pathophysiology, The School of Basic Medical Sciences, Chongqing Medical University, Chongqing 400016, China; Chongqing Key Laboratory of Maternal and Fetal Medicine, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China; Department of Obstetrics, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
Abstract:
Mitophagy plays a significant role in modulating the activation of pyrin domain-containing protein 3 (NLRP3) inflammasome, which is a major contributor to the inflammatory response that exacerbates cerebral ischemia-reperfusion (I/R) injury. Despite this, the transcriptional regulation mechanism that governs mitophagy remains unclear. This study sought to explore the potential mechanism of Forkhead Box P1 (Foxp1) and its impact on cerebral I/R injury. We investigated the potential neuroprotective role of Foxp1 in cerebral I/R injury by the middle cerebral artery occlusion (MCAO) mouse model. Additionally, we assessed whether FUN14 domain-containing protein 1 (FUNDC1) could rescue the protective effect of Foxp1. Our results showed that overexpression of Foxp1 prevented brain damage during cerebral I/R injury and promoted NLRP3 inflammasome activation, whereas knockdown of Foxp1 had the opposite effect. Notably, Foxp1 overexpression directly promotes FUNDC1 expression, enhanced mitophagy activation, and inhibited the inflammatory response mediated by the NLRP3 inflammasome. Furthermore, we confirmed through chromatin immunoprecipitation (ChIP) and luciferase reporter assays that FUNDC1 is a direct target gene of Foxp1 downstream. Furthermore, the knockdown of FUNDC1 reversed the increased activation of mitophagy and suppressed NLRP3 inflammasome activation induced by Foxp1 overexpression. Collectively, our findings suggest that Foxp1 inhibits NLRP3 inflammasome activation through FUNDC1 to reduce cerebral I/R injury.
Insights
Forkhead Box P1 (Foxp1) protects the brain from ischemia-reperfusion (I/R) injury by enhancing mitophagy. It achieves this by promoting FUNDC1 expression, which suppresses the NLRP3 inflammasome, reducing inflammation and brain damage.
Area of Science:
- Neuroscience
- Molecular Biology
- Immunology
Background:
- Mitophagy regulates the NLRP3 inflammasome, a key factor in inflammatory responses exacerbating cerebral ischemia-reperfusion (I/R) injury.
- The transcriptional mechanisms governing mitophagy, particularly in the context of I/R injury, are not fully understood.
Purpose of the Study:
- To investigate the role of Forkhead Box P1 (Foxp1) in cerebral I/R injury.
- To elucidate the mechanism by which Foxp1 influences mitophagy and NLRP3 inflammasome activation.
- To determine if FUNDC1 mediates the neuroprotective effects of Foxp1.
Main Methods:
- Utilized a middle cerebral artery occlusion (MCAO) mouse model to induce cerebral I/R injury.
- Assessed the effects of Foxp1 overexpression and knockdown on brain damage and inflammation.
- Employed chromatin immunoprecipitation (ChIP) and luciferase reporter assays to confirm the direct transcriptional regulation of FUNDC1 by Foxp1.
- Investigated the impact of FUNDC1 knockdown on mitophagy and NLRP3 inflammasome activation.
Main Results:
- Foxp1 overexpression conferred neuroprotection against cerebral I/R injury, while Foxp1 knockdown exacerbated damage.
- Foxp1 directly upregulated the expression of FUNDC1, a key mitophagy regulator.
- Foxp1 overexpression enhanced mitophagy and inhibited NLRP3 inflammasome activation, reducing inflammation.
- Knockdown of FUNDC1 reversed the mitophagy-promoting and NLRP3 inflammasome-inhibiting effects of Foxp1.
Conclusions:
- Foxp1 exerts a neuroprotective effect in cerebral I/R injury by directly targeting and upregulating FUNDC1.
- This Foxp1-FUNDC1 axis enhances mitophagy, leading to the suppression of NLRP3 inflammasome activation and subsequent reduction in inflammation.
- The findings reveal a novel transcriptional regulatory pathway involving Foxp1 and FUNDC1 in mitigating cerebral I/R injury.
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