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Nrf2-dependent effects of CDDO-Me on bactericidal activity in macrophage infection models
Therese B Deramaudt1, Ahmad Chehaitly1, Marcel Bonay1,2
1U1179 INSERM, END-ICAP, UFR des Sciences de la Santé-Simone Veil, Université de Versailles Saint-Quentin-en-Yvelines, Montigny-le-Bretonneux, France.
Introduction:
Diabetes and chronic kidney disease (CKD) increase susceptibility to bacterial infections, particularly Staphylococcus aureus, which is associated with highmortality in CKD patients. Dysregulated macrophage activity and excessive oxidative stress exacerbate immune dysfunction and inflammation in these conditions. Nrf2 (nuclear factor erythroid 2-related factor 2) is a key regulator of antioxidant defenses and macrophage function. CDDO-Me, a synthetic triterpenoid, activates Nrf2, providing antioxidant and anti-inflammatoryeffects. However, its precise role in modulating macrophage activity, polarization, and bacterial clearance remains unclear.
Methods:
The effects of CDDO-Me on macrophage function were evaluated in vitro (THP-1 and RAW 264.7 macrophages) and an in vivo Nrf2 knockout mouse model. Nrf2 activation was assessed via Western blot and luciferase reporter assays, oxidative stress was measured using CellROX reagent, and inflammatory responses were quantified by RT-qPCR. Intracellular S. aureus survival and macrophage polarization markers were analyzed to investigate the role of CDDO-Me in enhancing bactericidal activity.
Results:
Our results showed that CDDO-Me activated the Nrf2 signaling pathway, reducing oxidative stress and inflammation in macrophages by downregulating pro-inflammatory cytokines (IL-1β, TNF-α). It modulated macrophage polarization, decreasing M1 and M2 marker expression, and significantly enhanced bactericidal activity against S. aureus. These effects were Nrf2-dependent, as demonstrated in knockout models.
Conclusion:
The ability of CDDO-Me to regulate oxidative stress, inflammation, and bacterial clearance underscores its therapeutic potential for managing inflammatory and infectious diseases indiabetes and CKD.
Insights
CDDO-Me activates the Nrf2 pathway, reducing oxidative stress and inflammation in macrophages. This enhances bacterial clearance of Staphylococcus aureus, showing therapeutic potential for diabetes and CKD patients.
Area of Science:
- Immunology and Microbiology
- Molecular Biology and Pharmacology
Background:
- Diabetes and chronic kidney disease (CKD) elevate susceptibility to bacterial infections, particularly Staphylococcus aureus, leading to high mortality in CKD patients.
- Impaired macrophage function and heightened oxidative stress in diabetes and CKD contribute to immune dysfunction and inflammation.
- Nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial for antioxidant defense and macrophage regulation; its role in CDDO-Me's effects on macrophages and bacterial clearance is unclear.
Purpose of the Study:
- To investigate the effects of CDDO-Me on macrophage activity, polarization, and bacterial clearance in the context of Nrf2 activation.
- To elucidate the Nrf2-dependent mechanisms underlying CDDO-Me's modulation of oxidative stress, inflammation, and Staphylococcus aureus infection.
Main Methods:
- Evaluated CDDO-Me's impact on macrophage function in vitro (THP-1, RAW 264.7) and in vivo using Nrf2 knockout mice.
- Assessed Nrf2 activation via Western blot and luciferase assays; measured oxidative stress (CellROX) and inflammation (RT-qPCR).
- Analyzed intracellular Staphylococcus aureus survival and macrophage polarization markers to determine CDDO-Me's effect on bactericidal activity.
Main Results:
- CDDO-Me activated the Nrf2 signaling pathway, significantly reducing oxidative stress and inflammation in macrophages by downregulating IL-1β and TNF-α.
- CDDO-Me modulated macrophage polarization, decreasing both M1 and M2 marker expression.
- The compound markedly enhanced bactericidal activity against Staphylococcus aureus in an Nrf2-dependent manner.
Conclusions:
- CDDO-Me effectively regulates macrophage oxidative stress, inflammation, and bacterial clearance via Nrf2 activation.
- These findings highlight CDDO-Me's therapeutic potential for treating inflammatory and infectious diseases associated with diabetes and CKD.
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