1. Academic Validation
  2. Autophagy blockage promotes the pyroptosis of ox-LDL-treated macrophages by modulating the p62/Nrf2/ARE axis

Autophagy blockage promotes the pyroptosis of ox-LDL-treated macrophages by modulating the p62/Nrf2/ARE axis

  • J Physiol Biochem. 2021 Aug;77(3):419-429. doi: 10.1007/s13105-021-00811-2.
Jiaru Liu 1 Chao Wang 1 Jiashan Li 1 Ying Yu 1 Yuee Liu 1 Huihui Liu 1 Qi Peng 1 Xiuru Guan 2
Affiliations

Affiliations

  • 1 Department of Laboratory Diagnostics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, NanGang, Harbin, Heilongjiang, 150001, People's Republic of China.
  • 2 Department of Laboratory Diagnostics, the First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, NanGang, Harbin, Heilongjiang, 150001, People's Republic of China. gxr0451@sina.com.
Abstract

Atherosclerosis, a chronic comprehensive Cardiovascular Disease, is characterized by the lipid infiltration, formation of foam cells derived from macrophages and inflammation in the vessel wall. Substantial evidence confirms that the activity of autophagic bodies plays a pivot role in regulating cell deaths, but the mechanisms of Autophagy to regulate the Pyroptosis of macrophages in atherosclerosis remain unclear. In our study, we explored that ox-LDL decreased the cell viability and destroyed the integrity of cell membrane, resulting in the Pyroptosis of THP-1 derived macrophages in a dose-dependent manner. Western blotting, qRT-PCR and ELISA also showed that chloroquine (CQ) could up-regulate the expression of p62 through impairing Autophagy and induce the Pyroptosis of macrophages treated by ox-LDL, as evidenced by the decrease of cell viability and membrane integrity, and the increase of pro-caspase-1, GSDMD, and proinflammatory factors IL-1β and IL-18. Further researches demonstrated that Nrf2, a nuclear factor activated by p62, was linked to macrophage Pyroptosis. Overactivating or suppressing Nrf2/ARE signaling would correspondingly aggravate or alleviate Pyroptosis, in which the level of p62 was regulated by Nrf2 feedback. Then, bioinformatic analysis verified that there was a close interaction between p62, Nrf2/ARE signaling proteins and pyroptosis-related proteins. Taken together, our results show that blocking Autophagy promotes the Pyroptosis of ox-LDL-treated macrophages via the p62/Nrf2/ARE axis, providing a novel therapeutic target for atherosclerosis.

Keywords

Atherosclerosis; Autophagy; Nrf2/ARE pathway; Pyroptosis.

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