2. Academic Validation
  3. Bilirubin stabilizes the mitochondrial membranes during NLRP3 inflammasome activation

Bilirubin stabilizes the mitochondrial membranes during NLRP3 inflammasome activation

  • Biochem Pharmacol. 2022 Sep;203:115204. doi: 10.1016/j.bcp.2022.115204.
Yufei Li 1,  Hongda Sheng 1,  Ziwei Yan 1,  Bin Guan 2,  Shifa Qiang 2,  Jing Qian 3,  Yi Wang 4
Affiliations

Affiliations

  • 1 Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 2 Xiamen Traditional Chinese Medicine Co., Ltd., Xiamen 361100, China.
  • 3 Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua 321016, China. Electronic address: jingqian@zju.edu.cn.
  • 4 Pharmaceutical Informatics Institute, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China; Jinhua Institute of Zhejiang University, Jinhua 321016, China; Innovation Institute for Artificial Intelligence in Medicine of Zhejiang University, Hangzhou 310058, China; State Key Laboratory of Component-Based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China. Electronic address: wangyi@zju.edu.cn.
PMID: 35944727 DOI: 10.1016/j.bcp.2022.115204
Abstract

Mitochondria sense both intracellular and extracellular stress, with the subsequence released mt-ROS resulted from the interruption of its membrane integrity being a direct activator for NLRP3 inflammasome activation. Regulating the morphology and function of mitochondria could be a strategy against uncontrolled inflammation. We have previously reported that physiological concentrations of bilirubin exhibit anti-inflammatory effect by inhibiting both NF-κB and inflammasome activation. In the current study, we investigated its anti-NLRP3 inflammasome effect per se by means of detecting releasing of IL-1β and TNF-α, the formation of ASC oligomers and ASC-specks, as well as pro-caspase-1 recruitment. Mechanistically, with respect to the antioxidant nature of bilirubin, we evaluated the effect of bilirubin on the releasing of mt-ROS from mitochondria. In addition, mitochondrial morphofunction mainly including morphology and membrane potential in contact living macrophages was analyzed by applying a newly developed multiplexed high-content mitochondrial imaging analysis system using live-cell microscopy. We revealed that bilirubin targets and stabilizes mitochondrial membrane during NLRP3 inflammasome activation; defined doses of bilirubin could be considered as a mitochondria targeted medication against inflammasome-related diseases.

Keywords

Bilirubin; High-content imaging analysis; Mitochondrial morphofunction; NLRP3 inflammasome.

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