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Baicalein disrupts the KEAP1-NRF2 interaction to alleviate oxidative stress injury by inhibiting M1 macrophage
Fuyun Chi1, Chuanjing Cheng1, Kaixin Liu1
1State Key Laboratory of Medicinal Chemical Biology, College of Pharmacy and Tianjin Key Laboratory of Molecular Drug Research, Nankai University, Tianjin, 300353, China.
Abstract:
Macrophages are key players in maintaining the balance of tissues and dealing with inflammation, carrying out vital functions specific to different tissues while safeguarding the body against infections. The intricate interplay between oxidative stress and macrophage polarization and how this contributes to pneumonia is not fully understood. Herein, a predominant accumulation of baicalein in lung macrophages of pathogen-infected mice was observed by an alkynyl-modified probe. Baicalein effectively reduces oxidative stress in vivo and in vitro by modulating the KEAP1-NRF2/ARE signaling pathway. Further investigation indicated that baicalein has inhibitory effects on M1 macrophage polarization and phagocytic capacity, reducing inflammatory cytokine expression. As a protein-protein interaction (PPI) inhibitor, baicalein disrupts the KEAP1-NRF2 interaction by competitively binding to the DGR/Kelch domain of KEAP1. This process helps NRF2 move to the nucleus, which activates the antioxidant transcriptional program, suppresses the production of reactive oxygen species (ROS), and mitigates oxidative stress damage. These findings suggest a different approach to developing treatments for oxidative stress that focuses on inhibiting the interaction between KEAP1-NRF2.
Insights
Baicalein accumulation in lung macrophages reduces oxidative stress and inflammation by inhibiting the KEAP1-NRF2 interaction. This novel approach targets oxidative stress, offering potential treatments for conditions like pneumonia.
Area of Science:
- Immunology and Molecular Biology
- Cellular Biology and Biochemistry
Background:
- Macrophages are crucial for tissue homeostasis and immune responses.
- The link between oxidative stress, macrophage polarization, and pneumonia requires further elucidation.
Purpose of the Study:
- To investigate the role of baicalein in modulating oxidative stress and macrophage polarization in the context of pneumonia.
Main Methods:
- Utilized an alkynyl-modified probe to detect baicalein accumulation in lung macrophages of infected mice.
- Assessed baicalein's effects on oxidative stress, KEAP1-NRF2/ARE signaling, M1 macrophage polarization, and phagocytic capacity in vitro and in vivo.
- Characterized baicalein as a protein-protein interaction inhibitor disrupting the KEAP1-NRF2 interaction.
Main Results:
- Baicalein predominantly accumulated in lung macrophages during infection.
- Baicalein significantly reduced oxidative stress by modulating the KEAP1-NRF2/ARE pathway.
- Baicalein inhibited M1 macrophage polarization, decreased phagocytic capacity, and lowered inflammatory cytokine expression.
- Baicalein acts as a KEAP1-NRF2 interaction inhibitor, promoting nuclear translocation of NRF2 and activating antioxidant responses.
Conclusions:
- Baicalein mitigates oxidative stress and inflammation associated with pneumonia by inhibiting the KEAP1-NRF2 interaction.
- Targeting the KEAP1-NRF2 interaction with compounds like baicalein presents a promising therapeutic strategy for oxidative stress-related diseases.
