Nrf2 protects against cerebral ischemia-reperfusion injury by suppressing programmed necrosis and inflammatory signaling pathways

Weiwei Chen; Xue Teng; Hongmei Ding; Zhiyuan Xie; Ping Cheng; Zhihan Liu; Tao Feng; Xia Zhang; Wenjuan Huang; Deqin Geng

doi:10.21037/atm-22-604

Nrf2 protects against cerebral ischemia-reperfusion injury by suppressing programmed necrosis and inflammatory signaling pathways

Ann Transl Med. 2022 Mar;10(6):285. doi: 10.21037/atm-22-604.

Authors

Weiwei Chen^#^{1

2}, Xue Teng^#³, Hongmei Ding^{1

4}, Zhiyuan Xie⁵, Ping Cheng⁶, Zhihan Liu⁴, Tao Feng⁷, Xia Zhang², Wenjuan Huang², Deqin Geng^{1

4}

Affiliations

¹ Nanjing Medical University, Nanjing, China.
² Department of Neurology, Xuzhou Central Hospital, Xuzhou, China.
³ Nursing Department, Jiangsu Cancer Hospital & Jiangsu Institute of Cancer Research & The Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, China.
⁴ Department of Neurology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China.
⁵ Department of Gastrointestinal surgery, Xuzhou Central Hospital, Xuzhou, China.
⁶ Bengbu Medical College, Bengbu, China.
⁷ Department of Rehabilitation Medicine, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.

^# Contributed equally.

Abstract

Background: The NOD-like receptor family pyrin domain-containing 3 (NLRP3) -mediated neuroinflammation is linked to neuronal necroptosis in cerebral ischemia-reperfusion (I/R) injury, especially in cerebral ischemic penumbra. This study was designed to investigate the regulation of nuclear factor E2-related factor-2 (Nrf2) on NLRP3 inflammasome in necroptosis signal pathway induced by I/R injury.

Methods: We investigated the mechanisms of Nrf2-negative regulation in necroptosis signaling pathway by using middle cerebral artery occlusion (MCAO) with Q-VD-OPH injected intraperitoneally. The protein level of the NLRP3 inflammasome was detected by western blot with Nrf2 knockdown and overexpression. NLRP3 inflammasome activation was Reactive oxygen species (ROS) dependent, and the protein level was regulated when N-acetylcysteine (NAC) and adenosine triphosphate (ATP) were selected as tools for regulating ROS.

Results: We demonstrated the negative regulation of Nrf2 on NLRP3 inflammasome activation in Q-VD-OPH-induced necroptosis in cerebral artery I/R injury through Lentivirus-mediated RNA Interferenc, which mediated knockdown and overexpression of Nrf2. NLRP3 inflammasome activation was sensitive to both ATP-mediated ROS level increases and NAC-mediated ROS inhibition, suggesting that ROS is associated with the activation of NLRP3 inflammasome in necroptosis. In addition, Nrf2-induced NAD(P)H quinone dehydrogenase 1 (NQO1) was involved in the inhibition of NLRP3 inflammasome activation. These results suggest that Nrf2 regulates NQO1 to attenuate ROS, which negatively regulates NLRP3 inflammasome.

Conclusions: Nrf2/NQO1 was an inhibitor of ROS-induced NLRP3 inflammasome activation in Q-VD-OPH-induced necroptosis following cerebral I/R injury. Therefore, NLRP3 inflammasome could be a potential therapeutic target for cerebral ischemia.

Keywords: NAD(P)H quinone dehydrogenase 1 (NQO1); NLRP3 inflammasome; necroptosis; nuclear factor E2-related factor-2 (Nrf2); reactive oxygen species (ROS).