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Open AccessArticle

Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats

by 1,2,†, 2,3,†, 1,2, 2,3, 2,3,* and 1,2,*
1
Department of Pathophysiology, Chongqing Medical University, Chongqing 400010, China
2
Institute of Neuroscience, Chongqing Medical University, Chongqing 400010, China
3
Department of Pathology, Chongqing Medical University, Chongqing 400010, China
*
Authors to whom correspondence should be addressed.
These authors contributed equally to this work.
Cells 2019, 8(8), 897; https://doi.org/10.3390/cells8080897
Received: 23 July 2019 / Revised: 9 August 2019 / Accepted: 13 August 2019 / Published: 14 August 2019
(This article belongs to the Special Issue Study around Neuroinflammation)
Background: Nod-like receptor protein 3 (NLRP3) inflammasome is a crucial contributor in the inflammatory process during cerebral ischemia/reperfusion (I/R) injury. ATF4 plays a pivotal role in the pathogenesis of cerebral I/R injury, however, its function and underlying mechanism are not fully characterized yet. In the current study, we examined whether ATF4 ameliorates cerebral I/R injury by inhibiting NLRP3 inflammasome activation and whether mitophagy is involved in this process. In addition, we explored the role of parkin in ATF4-mediated protective effects. Method: To address these issues, healthy male adult Sprague-Dawley rats were exposed to middle cerebral artery occlusion for 1 h followed by 24 h reperfusion. Adeno-associated virus (AAV) and siRNA were injected into rats to overexpress and knockdown ATF4 expression, respectively. After pretreatment with AAV, mdivi-1(mitochondrial division inhibitor-1) was injected into rats to block mitophagy activity. Parkin expression was knockdown using specific siRNA after AAV pretreatment. Result: Data showed that ATF4 overexpression induced by AAV was protective against cerebral I/R injury, as evidenced by reduced cerebral infraction volume, decreased neurological scores and improved outcomes of HE and Nissl staining. In addition, overexpression of ATF4 gene was able to up-regulate Parkin expression, enhance mitophagy activity and inhibit NLRP3 inflammasome-mediated inflammatory response. ATF4 knockdown induced by siRNA resulted in the opposite effects. Furthermore, ATF4-mediated inhibition of NLRP3 inflammasome activation was strongly affected by mitophagy blockage upon mdivi-1 injection. Besides, ATF4-mediated increase of mitophagy activity and inhibition of NLRP3 inflammasome activation were effectively reversed by Parkin knockdown using siRNA. Conclusion: Our study demonstrated that ATF4 is able to alleviate cerebral I/R injury by suppressing NLRP3 inflammasome activation through parkin-dependent mitophagy activity. These results may provide a new strategy to relieve cerebral I/R injury by modulating mitophagy-NLRP3 inflammasome axis. View Full-Text
Keywords: ATF4; Parkin; mitophagy; NLRP3 inflammasome; ischemia-reperfusion; neuroprotection ATF4; Parkin; mitophagy; NLRP3 inflammasome; ischemia-reperfusion; neuroprotection
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MDPI and ACS Style

He, Q.; Li, Z.; Meng, C.; Wu, J.; Zhao, Y.; Zhao, J. Parkin-Dependent Mitophagy Is Required for the Inhibition of ATF4 on NLRP3 Inflammasome Activation in Cerebral Ischemia-Reperfusion Injury in Rats. Cells 2019, 8, 897.

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